Stratum oriens horizontal interneurone diversity and hippocampal network dynamics
1 Department of Physiology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA
Abstract
In this last decade, the combination of differential interference contrast infrared video technology and patch-clamp techniques applied to slices in vitro has allowed the routine electrophysiological recording of visually identified central neurones. This has opened the way to the possibility of preselecting GABAergic interneurones of the hippocampus on the basis of some peculiar morphological characteristics. In particular, stratum oriens ‘horizontal’ interneurones are easily recognizable in living hippocampal slices because of their location and bipolar/bitufted appearance. Thus, this class of cells has rapidly risen as one of the most studied in the entire hippocampus. In this review, I will try to assemble the vast electrophysiological knowledge on these interneurones into a more focused picture, which is relevant for network activity in vitro and in vivo.
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Hippocampal horizontal interneurones are diverse and include different proportions of specific cell types
Remarkably, Ramon y Cajal (1893) already described stratum oriens neurones with similar horizontal dendritic architecture, but he also noticed the possibility of different axonal projections. It is now established that, despite a roughly similar somatodendritic structure in stratum oriens, GABAergic output from horizontal interneurones can be channelled towards different and specific postsynaptic domains of the target pyramidal cells (Fig. 1). Based on this simple criterion (i.e. location of the soma and projection of the axon), horizontal interneurones have been named and divided into at least eight different groups. Oriens lacunosum-moleculare cells (O-LM cells) project their axon to stratum lacunosum-moleculare (for a summary of their properties see Maccaferri & Lacaille, 2003), oriens-bistratified (O-bistratified) cells innervate stratum oriens and stratum radiatum (Martina et al. 2000; Maccaferri et al. 2000; Losonczy et al. 2002), trilaminar cells send their axon to three layers (stratum oriens, pyramidale and radiatum: Sik et al. 1995; Gloveli et al. 2005), stratum oriens–stratum oriens (SO-SO) cells innervate stratum oriens locally (McBain et al. 1994; Hajos & Mody, 1997; Cossart et al. 1998; Martina et al. 2000; Lien et al. 2002), backprojection interneurones of the CA1 subfield innervate several layers of the CA3 region (Sik et al. 1994, 1995; Gloveli et al. 2005), horizontal basket cells target mostly stratum pyramidale (McBain et al. 1994; Maccaferri et al. 2000; Losonczy et al. 2002), horizontal axo-axonic cells (Ganter et al. 2004) establish selective contact with the axon initial segment of pyramidal neurones at the border between stratum oriens and stratum pyramidale, and, finally, hippocampo-septal projection interneurones specifically target extrahippocampal regions and hippocampal GABAergic cells (Gulyas et al. 2003). Other criteria have also been used for classification purposes like, for example, the expression of a variety of peptides (somatostatin, vasoactive intestinal polypeptide (VIP), cholecystokinin (CCK), etc.) and/or calcium binding proteins. However, no exclusive marker for specific cell-types has been found yet (Maccaferri & Lacaille, 2003). For example, somatostatin is expressed by more than a specific neuronal type and is found at least in O-LM and O-bistratified cells.
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Despite possessing similar soma and dendrites (red), the specific axonal (black) localization of stratum oriens horizontal neurones defines distinct cell types. Notice, for example, the differences in the reconstructions showing (left to right): an O-LM cell, horizontal (h) basket cell, O-bistratified cell, and a horizontal (h) axo-axonic interneurone. A schematic representation of a CA1 pyramidal neurone is depicted at the left for reference. The borders of the different hippocampal layers are marked by dotted lines. l-m: stratum-lacunosum-moleculare, r: stratum radiatum, p: stratum pyramidale, and o: stratum oriens. Figure from Maccaferri et al. (2000). The horizontal axo-axonic cell was reprinted with permission of Wiley-Liss, Inc., a subsidiary of John Wiley & Sons, Inc. 2004 Wiley-Liss, from Ganter et al. (2004).
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In theory, the relative proportion of different horizontal interneurone types in the hippocampal circuit can offer some initial insights about their specific impact on the network. Work from different groups focused on the electrophysiological properties of these cells reported a quite variable representation. Part of this variability is probably the unavoidable consequence of experimental noise deriving from different animal species, strain and stage of development used in the various studies. Nevertheless, some general results seem to be consistent across studies. For example, O-LM cells are likely to represent a large proportion of stratum oriens horizontal neurones in slices: values as high as 100% (Ali & Thomson, 1998; Wierenga & Wadman, 2003; Pouille & Scanziani, 2004), 80% (McBain et al. 1994; Lien et al. 2002), 55% (Martina et al. 2000), 45% (Maccaferri et al. 2000), and 30% (Losonczy et al. 2002) have been reported. O-bistratified are also found in high proportions ranging from 45% (Maccaferri et al. 2000) to 25% (Martina et al. 2000; Losonczy et al. 2002). In contrast, other cell types such as: horizontal basket cells (Maccaferri et al. 2000; Martina et al. 2000; but see also Losonczy et al. 2002), horizontal interneurones with local oriens axonal ramifications (McBain et al. 1994; Martina et al. 2000; Lien et al. 2002), horizontal axo-axonic cells (Ganter et al. 2004), hippocampo-septal (Gulyas et al. 2003), trilaminar (Sik et al. 1995; Gloveli et al. 2005) and backprojection neurones (Sik et al. 1994; Sik et al. 1995; Gloveli et al. 2005) are likely to be less represented in slices, and therefore more rarely encountered in electrophysiological studies ‘in vitro’. Although these numbers are suggestive, it is essential to underscore that electrophysiological studies in vitro are hardly ever based on random sampling of the recorded target cells. In addition, the slicing procedure itself could selectively damage specific classes of interneurones (Gulyas et al. 2003). Therefore, in the absence of exclusive molecular markers for each interneuronal type, the precise contribution of each cellular type to the network architecture of the hippocampus remains a very important question yet to be elucidated.
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Horizontal interneurones as hippocampal feedback regulators
The architecture of the hippocampus allows advantage to be taken of a well-organized and precisely layered network (Freund & Buzsaki, 1996). For example, the coalignment of the dendritic tree of ‘horizontal’ interneurones of stratum oriens with the recurrent collateral branches of the axons of pyramidal neurones suggests a special ‘presynaptic input–postsynaptic target’ relationship. This very crude observation predicts an important role of horizontal interneurones as feedback modulators of hippocampal activity. Lacaille et al. (1987) first reported unitary excitatory postsynaptic potentials (EPSPs) in pyramidal cell stratum oriens interneurones paired recordings, thus demonstrating the existence of a functional excitatory input originating from the recurrent collateral of CA1 pyramidal cells. Several studies have since converged in showing that CA1 horizontal interneurones are a preferential target of pyramidal cell recurrent collateral. The probability of finding connected pairs between CA1 pyramidal cells and interneurones is higher when the postsynaptic targets are horizontal cells compared to other types of interneurones. For example, the study by Ali & Thomson (1998) estimated a 33% probability of finding a connected pyramidal cell–horizontal interneurone pair, which compares to 5% or 14% in the case of unitary synaptic connections between pyramidal cells and conventional vertical basket or bistratified cells, respectively (Ali et al. 1998). Blasco-Ibanez & Freund (1995) estimated the proportion of excitatory synapses on the dendrites of somatostatin-immunopositive horizontal interneurones by taking advantage of selective ischaemic degeneration of CA1 pyramidal cells. Their results indicated that the vast majority (> 60%) of excitatory synapses on horizontal interneurones were originating from the local collateral of principal cells. Maccaferri & McBain (1995, 1996a) used a combination of field and whole-cell recordings to assess the dependency of the latency of the EPSP evoked in horizontal interneurones on the population spike recorded in pyramidal cells (Fig. 2). Horizontal interneurones were driven by the recurrent collateral of pyramidal cells to such a large extent that synaptic plasticity on pyramidal neurones was passively propagated to the target interneurones (Maccaferri & McBain, 1995). In conclusion, despite their large cellular variability, a common theme found in horizontal interneurones is feedback activation by the recurrent collateral of pyramidal cells. This role is especially crucial in the CA1 area, where pyramidal cells are the final output of the hippocampus and project processed information to extra-hippocampal regions. However, a highly homogeneous source of excitatory input does not necessarily translate in a similarly homogeneous pattern of activity for the different interneuronal subtypes. Transformation of feedback excitation of horizontal interneurones into action potentials leading to GABA release is bound to be determined by the specific synaptic and intrinsic properties expressed by each different cell type.
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A, after stimulation of stratum radiatum, the EPSP in a horizontal O-LM cell begins after the peak of the population spike recorded in stratum pyramidale, indicating that interneurone activation depends on firing of pyramidal cells. B, in contrast, the EPSP recorded in a stratum oriens basket cell with vertical dendrites begins before the peak of the population spike, indicating feedforward activation. Notice also the notch in the rising phase of the EPSP recorded in the vertical interneurone (arrow), suggesting distinct events mediated by mono- (feedforward) and disynaptic (feedback) inputs. Figure modified and reproduced with permission from Maccaferri & McBain (1996a). 1996 by the Society for Neuroscience.
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Synaptic excitation of horizontal interneurones
Horizontal interneurones express ionotropic glutamate receptors of the AMPA, NMDA and kainate families (Arancio et al. 1994; Morin et al. 1996; Cossart et al. 1998, 2002; Hajos et al. 2002; Nyiri et al. 2003), which contribute to their synaptic activation. The exact specific subunit composition and stochiometry, however, has not been determined and remains, at present unknown. The number of release sites at excitatory synaptic connections onto horizontal neurones of the CA3 region is likely to be very small. One study combining electrophysiology and electron microscopy demonstrated that hippocampal pyramidal cells can excite O-LM cells through a single release site in guinea pig slices in vitro (Gulyas et al. 1993). However, species-specific or regional differences may occur since unitary EPSPs recorded in the CA1 region of the rat were reported as big as 12 mV and short-term plasticity (facilitation) of the unitary EPSP could be clearly observed even in single sweeps (Lacaille et al. 1987; Ali & Thomson, 1998). Indeed, the type of short-term plasticity of the EPSP is an additional important feature differentiating specific classes of horizontal interneurones. Evidence for cell-type specificity of EPSP short-term plasticity was first shown for O-LM cells, whose excitatory input is facilitating (Ali & Thomson, 1998; Pouille & Scanziani, 2004). In contrast, horizontal axo-axonic cells display short-term depression (Ganter et al. 2004). The detailed study by Losonczy and collegues (2002) expanded these results and raised the possibility that the situation may be more complex and a certain degree of variability within the same interneurone subtype may exist. However, it also needs to be taken into consideration that experiments in this latter study were based on EPSPs recorded from local multifibre stimulations. Therefore, heterogeneity of the afferent input cannot be totally excluded. In summary, these studies suggest the intriguing possibility of activity-dependent recruitment of specific interneuronal types. While perisomatic-targeting neurones would act as coincidence detectors, dendritic-targeting O-LM cells would act as synaptic integrators of repetitive activity in the recurrent collateral of pyramidal cells (Pouille & Scanziani, 2004).
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In addition to ionotropic receptors, a series of metabotropic glutamate receptors also regulate synaptic transmission in distinct classes of horizontal interneurones (Shigemoto et al. 1996). For example, dendritic metabotropic glutamate receptors 1 (mGluR1a), are expressed by horizontal interneurones that are also positive for the molecular marker somatostatin (Baude et al. 1993; Freund & Buzsaki, 1996; Losonczy et al. 2002). These cells are likely to belong to the O-LM and O-bistratified groups (van Hooft et al. 2000; Losonczy et al. 2002; Ferraguti et al. 2004). Pharmacological activation of mGluRs with broad spectrum agonists generates oscillatory electrical activity and calcium elevations (McBain et al. 1994; Woodhall et al. 1999). Recent work has provided evidence for synaptic activation of mGluR1 in O-LM cells. A critical role in regulating the strength of this type of signalling is played by the intracellular calcium levels and by the clearance of glutamate mediated by astroglial glutamate transporters GLT-1 and GLAST (Huang et al. 2004). Thus, synaptic activation of mGlur1 on interneurones plays an essential role in the induction of cell-type specific long-term synaptic plasticity (Perez et al. 2001; Lapointe et al. 2004).
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GABAergic input and output of horizontal interneurones
Of all horizontal stratum oriens interneurones, GABAergic input has been studied most in O-LM cells. O-LM interneurones are densely innervated by a specific type of GABAergic cell called the IS-III (interneurone specific type III) cell, which expresses vasoactive intestinal polypeptide (VIP; Acsady et al. 1996). Septohippocampal inteneurones are a likely additional source of GABAergic input to this cell type (Gulyas et al. 1990). Lastly, reciprocal innervation between O-LM cells has been reported (Kogo et al. 2004). GABAergic input for other types of horizontal stratum oriens interneurones is less clear. VIP-immunoreactive fibres form a dense plexus in statum oriens and project mainly along the longitudinal axis of the hippocampus (Acsady et al. 1996). Consequently, it needs to be taken into consideration that the orientation of the slice cut can be an important variable in determining the level of fast inhibitory input received by these interneurones (Hajos & Mody, 1997). The loss of this specific inhibitory input may be, at least partially, responsible for the tonic firing that can be recorded in O-LM cells (McBain, 1994; Maccaferri & McBain, 1996b). The kinetic properties of spontaneous inhibitory postsynaptic currents (IPSCs) have been reported to be cell-type specific with a high variance, consistent with electrotonic filtering and possibly with different GABAA receptor subunit assemblies present at distinct synapses (Hajos & Mody, 1997). However, the pharmacological profile of miniature IPSCs in horizontal interneurones appears to be similar to the one of pyramidal cells (Patenaude et al. 2001). GABAergic input to horizontal stratum oriens interneurone is functionally down-regulated by group III metabotropic glutamate receptors: the presence of mGluR4, mGluR7 and mGluR8a has also been confirmed on the presynaptic active zone of GABAergic terminals impinging on the dendrites of this class of cells (Kogo et al. 2004).
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Voltage-clamp analysis of unitary GABAergic output originating from identified presynaptic horizontal stratum oriens interneurones suggested that the location of the postsynaptic domain has a profound impact in determining the kinetics of the IPSC recorded on the soma of the target pyramidal cell (Maccaferri et al. 2000). Accordingly, unitary IPSCs at more distal sites decreased in amplitude and showed slower kinetics. Thus, unitary IPSCs originating from O-LM cells have the smallest amplitude and slower kinetics, whereas perisomatic-targeting interneurones such as axo-axonic and basket cells generate fast and large amplitude IPSCs (Maccaferri et al. 2000; Ganter et al. 2004). Persistent firing activity in perisomatic- versus dendritic-targeting interneurones generates different responses in the postsynaptic cell. The short-term dynamics of the summated postsynaptic IPSCs originated by O-bistartified and O-LM cells are different from the one induced by basket and axo-axonic interneurones (Maccaferri et al. 2000). These properties, taken together with the previously discussed cell-type specificity of the EPSP short-term plasticity, would predict that information encoded by repetitive firing in the recurrent collateral of pyramidal cells may route fast inhibition to distinct postsynaptic domains in an activity-dependent fashion (Fig. 3).
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A, left, a train of action potentials (top) induced by a current step in a presynaptic horizontal axo-axonic cell induces a transient, depressing summated IPSC in a postsynaptic CA1 pyramidal cell. A single sweep (middle) and the average of many traces (bottom) are shown below. The dotted line indicates the baseline and the peak level of the first event. Right, similarly arranged traces from an O-bistratified pyramidal neurone unitary connection. A similar train of action potentials (top) induces a non-decremental summated postsynaptic response, as shown by a single sweep (middle) and by the average of many (bottom). Notice that the summated IPSC maintains a level of current similar to the peak of the first response throughout the action potential train. B, activity-dependent shift of postsynaptic inhibition from the perisomatic area to the dendrites. Activation of feedback inhibition by a single shock to the alveus (to activate antidromically the axon of CA1 pyramidal cells) is primarily channelled to the perisomatic area, whereas the last response of a three-shock stimulus at high frequency impacts primarily the dendrites. Traces from a simultaneous somatodendritic recording in a CA1 pyramidal neurone. Panel A is reproduced from Maccaferri et al. (2000). Panel B from Pouille & Scanziani (2004), is reproduced by permission for Nature429, 717–723, Macmillan Publishing Ltd (http://www.nature.com/).
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Intrinsic excitability and voltage-dependent conductances of horizontal interneurones
Stratum oriens horizontal cells are the interneurones in the hippocampus whose intrinsic properties have been more thoroughly investigated (Zhang & McBain, 1995a,b; Lien et al. 2002; Lien & Jonas, 2003). At least three main types of voltage-gated potassium conductances were found in a sample of horizontal cells mostly composed of O-LM interneurones: (i) a fast delayed rectifier highly sensitive to external 4-aminopyridine (4-AP) and teteraethylammonium (TEA), (ii) a slow delayed rectifier sensitive to high TEA concentrations, but 4-AP insensitive, and (iii) a rapidly inactivating A-type component blocked by high (mM) concentrations of 4-AP, but TEA resistant (Zhang & McBain, 1995a; Lien et al. 2002). Calcium-dependent potassium conductances are also expressed and play an important role in action potential repolarization (Zhang & McBain, 1995a,b). The properties of the fast delayed rectifier, corroborated by single-cell RT-PCR experiments, suggest the expression of Kv3 potassium conductances (Zhang & McBain, 1995a; Lien et al. 2002). These channels are optimized for high frequency spike generation and play an essential role in determining the firing pattern of these interneurones (Zhang & McBain, 1995b; Lien & Jonas, 2003). Topographically, potassium conductances of horizontal cells are expressed rather symmetrically in the two main dendritic branches, with just a slight tendency to increase distally (Martina et al. 2000). This dendritic expression and membrane localization is likely to play a role in regulating local excitability. A similar symmetrical distribution in the two main dendritic branches was found for sodium currents. However, in contrast to potassium conductances, their activation curves showed a certain degree of location dependency (Martina et al. 2000). This suggests the possibility of either domain-specific expression of different variants of channels or domain-specific regulation mediated by second messengers and regulatory enzymes (Gasparini & Magee, 2002). The high expression density of sodium channel was directly shown to allow dendritic initiation of action potentials, provided a sufficiently strong current stimulus. Therefore, in principle, horizontal interneurones possess variable action potential initiation sites, which may be selected according to the level of synaptic excitatory activity. Direct evidence for synaptic initiation of dendritic action potentials has not been shown yet. Another voltage-gated conductance that has been found expressed in horizontal neurones is responsible for the hyperpolarization-activated current (Ih), which shapes the typical sag response to hyperpolarizing current pulses (Maccaferri & McBain, 1996b). Ih contributes to setting the membrane potential and the spontaneous tonic firing of O-LM neurones in slices (Maccaferri & McBain, 1996b). A model of O-LM cells incorporating experimentally derived values for potassium and h conductances has been shown to reproduce several key properties such as current–frequency relationships and action potential multiple initiation sites (Saraga et al. 2003). In summary, the particular set of membrane intrinsic conductances expressed by horizontal interneurones appears to be very important for their frequency response to oscillatory input that shows a resonant peak at theta frequencies (Pike et al. 2000). Thus, the voltage-gated conductances of horizontal interneurones might be specifically suited to promoting activity during particular network states that are correlated with specific animal behaviour (Buzsaki et al. 1983; Freund & Buzsaki, 1996; Klausberger et al. 2003).
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Horizontal interneurones as elementary blocks of dynamic recurrent loops of the hippocampal network ‘in vitro’ and ‘in vivo’
The anatomical and physiological diversity of horizontal stratum oriens interneurones suggests that their activation by the recurrent collateral of pyramidal cells may generate a highly flexible feedback inhibition. Pouille & Scanziani (2004) have recently identified two broad sets of inhibitory circuits that can capture and transform the pattern of activity in the recurrent collaterals into specific spatiotemporal recurrent inhibition. Dendritic-targeting horizontal interneurones such as, for example, O-LM cells possess membrane time constant (Morin et al. 1996; Pouille & Scanziani, 2004), excitatory postsynaptic current kinetics (Pouille & Scanziani, 2004) and short-term plasticity (Ali & Thomson, 1998; Losonczy et al. 2002; Wierenega & Wadman, 2003; Pouille & Scanziani, 2004) very well suited to integrating incoming excitatory input into a repetitive train of action potentials. In addition, dendritic-targeting horizontal interneurones can maintain a relatively stable level of GABAA receptor-mediated current in their postsynaptic targets (Maccaferri et al. 2000). In contrast, perisomatic-targeting cells are more suited for a transient activation (Pouille & Scanziani, 2004; Ganter et al. 2004), and are endowed with a depressing GABAergic synapse on the postsynaptic targets (Maccaferri et al. 2000). As predicted by all these features, an activity-dependent shift of recurrent inhibition along the somatodendritic axis of pyramidal cells was directly observed by Pouille & Scanziani (2004) after activation of feedback inhibitory loops. Transient activity in recurrent inhibition primarily affected postsynaptic perisomatic domains, whereas persistent activity was channelled predominantly to the dendrites. This finding is likely to be relevant for a variety of physiological and/or pathological activity. Recent work from Gloveli et al. (2005) has shown that during kainate-induced gamma oscillations in vitro, O-LM and trilaminar cells fire at different frequencies despite the similarity of the excitatory input. Thus, modulation of O-LM firing by voltage gated conductances (Pike et al. 2000) during oscillatory gamma input could still produce dendritic hyperpolarization at theta frequency and explain nested oscillatory rhythms ‘in vivo’ (Gloveli et al. 2005). Furthermore, recent work ‘in vivo’ has shown that hippocampal theta activity can recruit firing in O-LM interneurones particularly effectively (Klausberger et al. 2003). The postsynaptic effect of O-LM interneurones on the distal dendrites of pyramidal cells may play a crucial role in regulating out-of-phase oscillations in the somatic and dendritic compartments and control the advancement of spike discharges observed in the behaving animal (Kamondi et al. 1998).
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In an ‘acute’ model of epileptiform activity, horizontal interneurones of the CA1 and CA3 region have been shown to burst synchronously with pyramidal cell (McBain, 1994; Aradi & Maccaferri, 2004). Quite intriguingly, horizontal interneurones seem to be more excitable than pyramidal cells and the latency to the first spike of the burst is shorter when compared to pyramidal neurones (Fig. 4). A potential explanation lies in the cell-type specificity of the inhibitory GABAergic input at the beginning of a burst cycle that regulates pyramidal cell, but not interneurone, excitability (Aradi & Maccaferri, 2004). In a chronic animal model of epilepsy, a selective vulnerability of somatostatin-immunoreactive horizontal neurones (likely to be O-LM or O-bistratified cells) has been observed, suggesting that the lack of recurrent dendritic inhibition may also play an important role in releasing epileptiform activity (Cossart et al. 2001).
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A, left, simultaneous recording from a CA3 horizontal interneurone (int) and pyramidal cell (pyr) in a hippocampal slice in vitro exposed to elevated external potassium concentrations (8.5 mM). Notice the synchronous bursting and the stronger activity in the interneurone. The right panel shows a burst at a magnified temporal scale: notice that firing in the interneurone precedes firing in the pyramidal cell. B, blocking fast inhibitory synaptic transmission with gabazine reduces the latency to the first spike during a burst in pyramidal cells (pyr), but not interneurones (int). Averaged sweeps of spontaneous bursts recorded in pyramidal cells and interneurones in control (c) and after the addition of gabazine (g). Bursts were artificially aligned on the first spike. Notice that the early phase of the burst leading to the first action potential is subjected to inhibitory control in pyramidal cells, but not interneurones. C, cell-type specific dynamics of GABAA receptor-mediated inhibition. Voltage-clamp recordings at 0 mV show a different kinetics in pyramidal cells versus interneurones. Notice an early component of the inhibitory waveform that is present in pyramidal cells, but absent in interneurones. Figure modified and reproduced with permission from Aradi & Maccaferri (2004). 2004 by the Society for Neuroscience.
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Conclusions
Despite many pieces of the puzzle being still missing, the concerted effort of collecting high-resolution experimental data on the properties of specific interneurone types is providing important insights on their role in central networks. The focus of electrophysiological research on hippocampal stratum oriens horizontal interneurones may have been initially prompted by a trivial technical advantage, such as their stereotypical dendritic orientation. However, it is now clear that this class of cells possesses many more reasons that make it of extreme interest for investigators. The convergence of the attention of molecular, cellular and system neuroscientists on this lucky type of neurone is bound to produce new fruitful discoveries for years to come.
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Footnotes
Dedicated to the memory of the late Eberhard H. Buhl, friend and colleague. This report was presented at The Journal of Physiology Symposium in honour of the late Eberhard H. Buhl on Structure/Function Correlates in Neurons and Networks, Leeds, UK, 10 September 2004. It was commissioned by the Editorial Board and reflects the views of the author.
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Abstract
In this last decade, the combination of differential interference contrast infrared video technology and patch-clamp techniques applied to slices in vitro has allowed the routine electrophysiological recording of visually identified central neurones. This has opened the way to the possibility of preselecting GABAergic interneurones of the hippocampus on the basis of some peculiar morphological characteristics. In particular, stratum oriens ‘horizontal’ interneurones are easily recognizable in living hippocampal slices because of their location and bipolar/bitufted appearance. Thus, this class of cells has rapidly risen as one of the most studied in the entire hippocampus. In this review, I will try to assemble the vast electrophysiological knowledge on these interneurones into a more focused picture, which is relevant for network activity in vitro and in vivo.
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Hippocampal horizontal interneurones are diverse and include different proportions of specific cell types
Remarkably, Ramon y Cajal (1893) already described stratum oriens neurones with similar horizontal dendritic architecture, but he also noticed the possibility of different axonal projections. It is now established that, despite a roughly similar somatodendritic structure in stratum oriens, GABAergic output from horizontal interneurones can be channelled towards different and specific postsynaptic domains of the target pyramidal cells (Fig. 1). Based on this simple criterion (i.e. location of the soma and projection of the axon), horizontal interneurones have been named and divided into at least eight different groups. Oriens lacunosum-moleculare cells (O-LM cells) project their axon to stratum lacunosum-moleculare (for a summary of their properties see Maccaferri & Lacaille, 2003), oriens-bistratified (O-bistratified) cells innervate stratum oriens and stratum radiatum (Martina et al. 2000; Maccaferri et al. 2000; Losonczy et al. 2002), trilaminar cells send their axon to three layers (stratum oriens, pyramidale and radiatum: Sik et al. 1995; Gloveli et al. 2005), stratum oriens–stratum oriens (SO-SO) cells innervate stratum oriens locally (McBain et al. 1994; Hajos & Mody, 1997; Cossart et al. 1998; Martina et al. 2000; Lien et al. 2002), backprojection interneurones of the CA1 subfield innervate several layers of the CA3 region (Sik et al. 1994, 1995; Gloveli et al. 2005), horizontal basket cells target mostly stratum pyramidale (McBain et al. 1994; Maccaferri et al. 2000; Losonczy et al. 2002), horizontal axo-axonic cells (Ganter et al. 2004) establish selective contact with the axon initial segment of pyramidal neurones at the border between stratum oriens and stratum pyramidale, and, finally, hippocampo-septal projection interneurones specifically target extrahippocampal regions and hippocampal GABAergic cells (Gulyas et al. 2003). Other criteria have also been used for classification purposes like, for example, the expression of a variety of peptides (somatostatin, vasoactive intestinal polypeptide (VIP), cholecystokinin (CCK), etc.) and/or calcium binding proteins. However, no exclusive marker for specific cell-types has been found yet (Maccaferri & Lacaille, 2003). For example, somatostatin is expressed by more than a specific neuronal type and is found at least in O-LM and O-bistratified cells.
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Despite possessing similar soma and dendrites (red), the specific axonal (black) localization of stratum oriens horizontal neurones defines distinct cell types. Notice, for example, the differences in the reconstructions showing (left to right): an O-LM cell, horizontal (h) basket cell, O-bistratified cell, and a horizontal (h) axo-axonic interneurone. A schematic representation of a CA1 pyramidal neurone is depicted at the left for reference. The borders of the different hippocampal layers are marked by dotted lines. l-m: stratum-lacunosum-moleculare, r: stratum radiatum, p: stratum pyramidale, and o: stratum oriens. Figure from Maccaferri et al. (2000). The horizontal axo-axonic cell was reprinted with permission of Wiley-Liss, Inc., a subsidiary of John Wiley & Sons, Inc. 2004 Wiley-Liss, from Ganter et al. (2004).
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In theory, the relative proportion of different horizontal interneurone types in the hippocampal circuit can offer some initial insights about their specific impact on the network. Work from different groups focused on the electrophysiological properties of these cells reported a quite variable representation. Part of this variability is probably the unavoidable consequence of experimental noise deriving from different animal species, strain and stage of development used in the various studies. Nevertheless, some general results seem to be consistent across studies. For example, O-LM cells are likely to represent a large proportion of stratum oriens horizontal neurones in slices: values as high as 100% (Ali & Thomson, 1998; Wierenga & Wadman, 2003; Pouille & Scanziani, 2004), 80% (McBain et al. 1994; Lien et al. 2002), 55% (Martina et al. 2000), 45% (Maccaferri et al. 2000), and 30% (Losonczy et al. 2002) have been reported. O-bistratified are also found in high proportions ranging from 45% (Maccaferri et al. 2000) to 25% (Martina et al. 2000; Losonczy et al. 2002). In contrast, other cell types such as: horizontal basket cells (Maccaferri et al. 2000; Martina et al. 2000; but see also Losonczy et al. 2002), horizontal interneurones with local oriens axonal ramifications (McBain et al. 1994; Martina et al. 2000; Lien et al. 2002), horizontal axo-axonic cells (Ganter et al. 2004), hippocampo-septal (Gulyas et al. 2003), trilaminar (Sik et al. 1995; Gloveli et al. 2005) and backprojection neurones (Sik et al. 1994; Sik et al. 1995; Gloveli et al. 2005) are likely to be less represented in slices, and therefore more rarely encountered in electrophysiological studies ‘in vitro’. Although these numbers are suggestive, it is essential to underscore that electrophysiological studies in vitro are hardly ever based on random sampling of the recorded target cells. In addition, the slicing procedure itself could selectively damage specific classes of interneurones (Gulyas et al. 2003). Therefore, in the absence of exclusive molecular markers for each interneuronal type, the precise contribution of each cellular type to the network architecture of the hippocampus remains a very important question yet to be elucidated.
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Horizontal interneurones as hippocampal feedback regulators
The architecture of the hippocampus allows advantage to be taken of a well-organized and precisely layered network (Freund & Buzsaki, 1996). For example, the coalignment of the dendritic tree of ‘horizontal’ interneurones of stratum oriens with the recurrent collateral branches of the axons of pyramidal neurones suggests a special ‘presynaptic input–postsynaptic target’ relationship. This very crude observation predicts an important role of horizontal interneurones as feedback modulators of hippocampal activity. Lacaille et al. (1987) first reported unitary excitatory postsynaptic potentials (EPSPs) in pyramidal cell stratum oriens interneurones paired recordings, thus demonstrating the existence of a functional excitatory input originating from the recurrent collateral of CA1 pyramidal cells. Several studies have since converged in showing that CA1 horizontal interneurones are a preferential target of pyramidal cell recurrent collateral. The probability of finding connected pairs between CA1 pyramidal cells and interneurones is higher when the postsynaptic targets are horizontal cells compared to other types of interneurones. For example, the study by Ali & Thomson (1998) estimated a 33% probability of finding a connected pyramidal cell–horizontal interneurone pair, which compares to 5% or 14% in the case of unitary synaptic connections between pyramidal cells and conventional vertical basket or bistratified cells, respectively (Ali et al. 1998). Blasco-Ibanez & Freund (1995) estimated the proportion of excitatory synapses on the dendrites of somatostatin-immunopositive horizontal interneurones by taking advantage of selective ischaemic degeneration of CA1 pyramidal cells. Their results indicated that the vast majority (> 60%) of excitatory synapses on horizontal interneurones were originating from the local collateral of principal cells. Maccaferri & McBain (1995, 1996a) used a combination of field and whole-cell recordings to assess the dependency of the latency of the EPSP evoked in horizontal interneurones on the population spike recorded in pyramidal cells (Fig. 2). Horizontal interneurones were driven by the recurrent collateral of pyramidal cells to such a large extent that synaptic plasticity on pyramidal neurones was passively propagated to the target interneurones (Maccaferri & McBain, 1995). In conclusion, despite their large cellular variability, a common theme found in horizontal interneurones is feedback activation by the recurrent collateral of pyramidal cells. This role is especially crucial in the CA1 area, where pyramidal cells are the final output of the hippocampus and project processed information to extra-hippocampal regions. However, a highly homogeneous source of excitatory input does not necessarily translate in a similarly homogeneous pattern of activity for the different interneuronal subtypes. Transformation of feedback excitation of horizontal interneurones into action potentials leading to GABA release is bound to be determined by the specific synaptic and intrinsic properties expressed by each different cell type.
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A, after stimulation of stratum radiatum, the EPSP in a horizontal O-LM cell begins after the peak of the population spike recorded in stratum pyramidale, indicating that interneurone activation depends on firing of pyramidal cells. B, in contrast, the EPSP recorded in a stratum oriens basket cell with vertical dendrites begins before the peak of the population spike, indicating feedforward activation. Notice also the notch in the rising phase of the EPSP recorded in the vertical interneurone (arrow), suggesting distinct events mediated by mono- (feedforward) and disynaptic (feedback) inputs. Figure modified and reproduced with permission from Maccaferri & McBain (1996a). 1996 by the Society for Neuroscience.
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Synaptic excitation of horizontal interneurones
Horizontal interneurones express ionotropic glutamate receptors of the AMPA, NMDA and kainate families (Arancio et al. 1994; Morin et al. 1996; Cossart et al. 1998, 2002; Hajos et al. 2002; Nyiri et al. 2003), which contribute to their synaptic activation. The exact specific subunit composition and stochiometry, however, has not been determined and remains, at present unknown. The number of release sites at excitatory synaptic connections onto horizontal neurones of the CA3 region is likely to be very small. One study combining electrophysiology and electron microscopy demonstrated that hippocampal pyramidal cells can excite O-LM cells through a single release site in guinea pig slices in vitro (Gulyas et al. 1993). However, species-specific or regional differences may occur since unitary EPSPs recorded in the CA1 region of the rat were reported as big as 12 mV and short-term plasticity (facilitation) of the unitary EPSP could be clearly observed even in single sweeps (Lacaille et al. 1987; Ali & Thomson, 1998). Indeed, the type of short-term plasticity of the EPSP is an additional important feature differentiating specific classes of horizontal interneurones. Evidence for cell-type specificity of EPSP short-term plasticity was first shown for O-LM cells, whose excitatory input is facilitating (Ali & Thomson, 1998; Pouille & Scanziani, 2004). In contrast, horizontal axo-axonic cells display short-term depression (Ganter et al. 2004). The detailed study by Losonczy and collegues (2002) expanded these results and raised the possibility that the situation may be more complex and a certain degree of variability within the same interneurone subtype may exist. However, it also needs to be taken into consideration that experiments in this latter study were based on EPSPs recorded from local multifibre stimulations. Therefore, heterogeneity of the afferent input cannot be totally excluded. In summary, these studies suggest the intriguing possibility of activity-dependent recruitment of specific interneuronal types. While perisomatic-targeting neurones would act as coincidence detectors, dendritic-targeting O-LM cells would act as synaptic integrators of repetitive activity in the recurrent collateral of pyramidal cells (Pouille & Scanziani, 2004).
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In addition to ionotropic receptors, a series of metabotropic glutamate receptors also regulate synaptic transmission in distinct classes of horizontal interneurones (Shigemoto et al. 1996). For example, dendritic metabotropic glutamate receptors 1 (mGluR1a), are expressed by horizontal interneurones that are also positive for the molecular marker somatostatin (Baude et al. 1993; Freund & Buzsaki, 1996; Losonczy et al. 2002). These cells are likely to belong to the O-LM and O-bistratified groups (van Hooft et al. 2000; Losonczy et al. 2002; Ferraguti et al. 2004). Pharmacological activation of mGluRs with broad spectrum agonists generates oscillatory electrical activity and calcium elevations (McBain et al. 1994; Woodhall et al. 1999). Recent work has provided evidence for synaptic activation of mGluR1 in O-LM cells. A critical role in regulating the strength of this type of signalling is played by the intracellular calcium levels and by the clearance of glutamate mediated by astroglial glutamate transporters GLT-1 and GLAST (Huang et al. 2004). Thus, synaptic activation of mGlur1 on interneurones plays an essential role in the induction of cell-type specific long-term synaptic plasticity (Perez et al. 2001; Lapointe et al. 2004).
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GABAergic input and output of horizontal interneurones
Of all horizontal stratum oriens interneurones, GABAergic input has been studied most in O-LM cells. O-LM interneurones are densely innervated by a specific type of GABAergic cell called the IS-III (interneurone specific type III) cell, which expresses vasoactive intestinal polypeptide (VIP; Acsady et al. 1996). Septohippocampal inteneurones are a likely additional source of GABAergic input to this cell type (Gulyas et al. 1990). Lastly, reciprocal innervation between O-LM cells has been reported (Kogo et al. 2004). GABAergic input for other types of horizontal stratum oriens interneurones is less clear. VIP-immunoreactive fibres form a dense plexus in statum oriens and project mainly along the longitudinal axis of the hippocampus (Acsady et al. 1996). Consequently, it needs to be taken into consideration that the orientation of the slice cut can be an important variable in determining the level of fast inhibitory input received by these interneurones (Hajos & Mody, 1997). The loss of this specific inhibitory input may be, at least partially, responsible for the tonic firing that can be recorded in O-LM cells (McBain, 1994; Maccaferri & McBain, 1996b). The kinetic properties of spontaneous inhibitory postsynaptic currents (IPSCs) have been reported to be cell-type specific with a high variance, consistent with electrotonic filtering and possibly with different GABAA receptor subunit assemblies present at distinct synapses (Hajos & Mody, 1997). However, the pharmacological profile of miniature IPSCs in horizontal interneurones appears to be similar to the one of pyramidal cells (Patenaude et al. 2001). GABAergic input to horizontal stratum oriens interneurone is functionally down-regulated by group III metabotropic glutamate receptors: the presence of mGluR4, mGluR7 and mGluR8a has also been confirmed on the presynaptic active zone of GABAergic terminals impinging on the dendrites of this class of cells (Kogo et al. 2004).
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Voltage-clamp analysis of unitary GABAergic output originating from identified presynaptic horizontal stratum oriens interneurones suggested that the location of the postsynaptic domain has a profound impact in determining the kinetics of the IPSC recorded on the soma of the target pyramidal cell (Maccaferri et al. 2000). Accordingly, unitary IPSCs at more distal sites decreased in amplitude and showed slower kinetics. Thus, unitary IPSCs originating from O-LM cells have the smallest amplitude and slower kinetics, whereas perisomatic-targeting interneurones such as axo-axonic and basket cells generate fast and large amplitude IPSCs (Maccaferri et al. 2000; Ganter et al. 2004). Persistent firing activity in perisomatic- versus dendritic-targeting interneurones generates different responses in the postsynaptic cell. The short-term dynamics of the summated postsynaptic IPSCs originated by O-bistartified and O-LM cells are different from the one induced by basket and axo-axonic interneurones (Maccaferri et al. 2000). These properties, taken together with the previously discussed cell-type specificity of the EPSP short-term plasticity, would predict that information encoded by repetitive firing in the recurrent collateral of pyramidal cells may route fast inhibition to distinct postsynaptic domains in an activity-dependent fashion (Fig. 3).
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A, left, a train of action potentials (top) induced by a current step in a presynaptic horizontal axo-axonic cell induces a transient, depressing summated IPSC in a postsynaptic CA1 pyramidal cell. A single sweep (middle) and the average of many traces (bottom) are shown below. The dotted line indicates the baseline and the peak level of the first event. Right, similarly arranged traces from an O-bistratified pyramidal neurone unitary connection. A similar train of action potentials (top) induces a non-decremental summated postsynaptic response, as shown by a single sweep (middle) and by the average of many (bottom). Notice that the summated IPSC maintains a level of current similar to the peak of the first response throughout the action potential train. B, activity-dependent shift of postsynaptic inhibition from the perisomatic area to the dendrites. Activation of feedback inhibition by a single shock to the alveus (to activate antidromically the axon of CA1 pyramidal cells) is primarily channelled to the perisomatic area, whereas the last response of a three-shock stimulus at high frequency impacts primarily the dendrites. Traces from a simultaneous somatodendritic recording in a CA1 pyramidal neurone. Panel A is reproduced from Maccaferri et al. (2000). Panel B from Pouille & Scanziani (2004), is reproduced by permission for Nature429, 717–723, Macmillan Publishing Ltd (http://www.nature.com/).
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Intrinsic excitability and voltage-dependent conductances of horizontal interneurones
Stratum oriens horizontal cells are the interneurones in the hippocampus whose intrinsic properties have been more thoroughly investigated (Zhang & McBain, 1995a,b; Lien et al. 2002; Lien & Jonas, 2003). At least three main types of voltage-gated potassium conductances were found in a sample of horizontal cells mostly composed of O-LM interneurones: (i) a fast delayed rectifier highly sensitive to external 4-aminopyridine (4-AP) and teteraethylammonium (TEA), (ii) a slow delayed rectifier sensitive to high TEA concentrations, but 4-AP insensitive, and (iii) a rapidly inactivating A-type component blocked by high (mM) concentrations of 4-AP, but TEA resistant (Zhang & McBain, 1995a; Lien et al. 2002). Calcium-dependent potassium conductances are also expressed and play an important role in action potential repolarization (Zhang & McBain, 1995a,b). The properties of the fast delayed rectifier, corroborated by single-cell RT-PCR experiments, suggest the expression of Kv3 potassium conductances (Zhang & McBain, 1995a; Lien et al. 2002). These channels are optimized for high frequency spike generation and play an essential role in determining the firing pattern of these interneurones (Zhang & McBain, 1995b; Lien & Jonas, 2003). Topographically, potassium conductances of horizontal cells are expressed rather symmetrically in the two main dendritic branches, with just a slight tendency to increase distally (Martina et al. 2000). This dendritic expression and membrane localization is likely to play a role in regulating local excitability. A similar symmetrical distribution in the two main dendritic branches was found for sodium currents. However, in contrast to potassium conductances, their activation curves showed a certain degree of location dependency (Martina et al. 2000). This suggests the possibility of either domain-specific expression of different variants of channels or domain-specific regulation mediated by second messengers and regulatory enzymes (Gasparini & Magee, 2002). The high expression density of sodium channel was directly shown to allow dendritic initiation of action potentials, provided a sufficiently strong current stimulus. Therefore, in principle, horizontal interneurones possess variable action potential initiation sites, which may be selected according to the level of synaptic excitatory activity. Direct evidence for synaptic initiation of dendritic action potentials has not been shown yet. Another voltage-gated conductance that has been found expressed in horizontal neurones is responsible for the hyperpolarization-activated current (Ih), which shapes the typical sag response to hyperpolarizing current pulses (Maccaferri & McBain, 1996b). Ih contributes to setting the membrane potential and the spontaneous tonic firing of O-LM neurones in slices (Maccaferri & McBain, 1996b). A model of O-LM cells incorporating experimentally derived values for potassium and h conductances has been shown to reproduce several key properties such as current–frequency relationships and action potential multiple initiation sites (Saraga et al. 2003). In summary, the particular set of membrane intrinsic conductances expressed by horizontal interneurones appears to be very important for their frequency response to oscillatory input that shows a resonant peak at theta frequencies (Pike et al. 2000). Thus, the voltage-gated conductances of horizontal interneurones might be specifically suited to promoting activity during particular network states that are correlated with specific animal behaviour (Buzsaki et al. 1983; Freund & Buzsaki, 1996; Klausberger et al. 2003).
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Horizontal interneurones as elementary blocks of dynamic recurrent loops of the hippocampal network ‘in vitro’ and ‘in vivo’
The anatomical and physiological diversity of horizontal stratum oriens interneurones suggests that their activation by the recurrent collateral of pyramidal cells may generate a highly flexible feedback inhibition. Pouille & Scanziani (2004) have recently identified two broad sets of inhibitory circuits that can capture and transform the pattern of activity in the recurrent collaterals into specific spatiotemporal recurrent inhibition. Dendritic-targeting horizontal interneurones such as, for example, O-LM cells possess membrane time constant (Morin et al. 1996; Pouille & Scanziani, 2004), excitatory postsynaptic current kinetics (Pouille & Scanziani, 2004) and short-term plasticity (Ali & Thomson, 1998; Losonczy et al. 2002; Wierenega & Wadman, 2003; Pouille & Scanziani, 2004) very well suited to integrating incoming excitatory input into a repetitive train of action potentials. In addition, dendritic-targeting horizontal interneurones can maintain a relatively stable level of GABAA receptor-mediated current in their postsynaptic targets (Maccaferri et al. 2000). In contrast, perisomatic-targeting cells are more suited for a transient activation (Pouille & Scanziani, 2004; Ganter et al. 2004), and are endowed with a depressing GABAergic synapse on the postsynaptic targets (Maccaferri et al. 2000). As predicted by all these features, an activity-dependent shift of recurrent inhibition along the somatodendritic axis of pyramidal cells was directly observed by Pouille & Scanziani (2004) after activation of feedback inhibitory loops. Transient activity in recurrent inhibition primarily affected postsynaptic perisomatic domains, whereas persistent activity was channelled predominantly to the dendrites. This finding is likely to be relevant for a variety of physiological and/or pathological activity. Recent work from Gloveli et al. (2005) has shown that during kainate-induced gamma oscillations in vitro, O-LM and trilaminar cells fire at different frequencies despite the similarity of the excitatory input. Thus, modulation of O-LM firing by voltage gated conductances (Pike et al. 2000) during oscillatory gamma input could still produce dendritic hyperpolarization at theta frequency and explain nested oscillatory rhythms ‘in vivo’ (Gloveli et al. 2005). Furthermore, recent work ‘in vivo’ has shown that hippocampal theta activity can recruit firing in O-LM interneurones particularly effectively (Klausberger et al. 2003). The postsynaptic effect of O-LM interneurones on the distal dendrites of pyramidal cells may play a crucial role in regulating out-of-phase oscillations in the somatic and dendritic compartments and control the advancement of spike discharges observed in the behaving animal (Kamondi et al. 1998).
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In an ‘acute’ model of epileptiform activity, horizontal interneurones of the CA1 and CA3 region have been shown to burst synchronously with pyramidal cell (McBain, 1994; Aradi & Maccaferri, 2004). Quite intriguingly, horizontal interneurones seem to be more excitable than pyramidal cells and the latency to the first spike of the burst is shorter when compared to pyramidal neurones (Fig. 4). A potential explanation lies in the cell-type specificity of the inhibitory GABAergic input at the beginning of a burst cycle that regulates pyramidal cell, but not interneurone, excitability (Aradi & Maccaferri, 2004). In a chronic animal model of epilepsy, a selective vulnerability of somatostatin-immunoreactive horizontal neurones (likely to be O-LM or O-bistratified cells) has been observed, suggesting that the lack of recurrent dendritic inhibition may also play an important role in releasing epileptiform activity (Cossart et al. 2001).
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A, left, simultaneous recording from a CA3 horizontal interneurone (int) and pyramidal cell (pyr) in a hippocampal slice in vitro exposed to elevated external potassium concentrations (8.5 mM). Notice the synchronous bursting and the stronger activity in the interneurone. The right panel shows a burst at a magnified temporal scale: notice that firing in the interneurone precedes firing in the pyramidal cell. B, blocking fast inhibitory synaptic transmission with gabazine reduces the latency to the first spike during a burst in pyramidal cells (pyr), but not interneurones (int). Averaged sweeps of spontaneous bursts recorded in pyramidal cells and interneurones in control (c) and after the addition of gabazine (g). Bursts were artificially aligned on the first spike. Notice that the early phase of the burst leading to the first action potential is subjected to inhibitory control in pyramidal cells, but not interneurones. C, cell-type specific dynamics of GABAA receptor-mediated inhibition. Voltage-clamp recordings at 0 mV show a different kinetics in pyramidal cells versus interneurones. Notice an early component of the inhibitory waveform that is present in pyramidal cells, but absent in interneurones. Figure modified and reproduced with permission from Aradi & Maccaferri (2004). 2004 by the Society for Neuroscience.
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Conclusions
Despite many pieces of the puzzle being still missing, the concerted effort of collecting high-resolution experimental data on the properties of specific interneurone types is providing important insights on their role in central networks. The focus of electrophysiological research on hippocampal stratum oriens horizontal interneurones may have been initially prompted by a trivial technical advantage, such as their stereotypical dendritic orientation. However, it is now clear that this class of cells possesses many more reasons that make it of extreme interest for investigators. The convergence of the attention of molecular, cellular and system neuroscientists on this lucky type of neurone is bound to produce new fruitful discoveries for years to come.
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Footnotes
Dedicated to the memory of the late Eberhard H. Buhl, friend and colleague. This report was presented at The Journal of Physiology Symposium in honour of the late Eberhard H. Buhl on Structure/Function Correlates in Neurons and Networks, Leeds, UK, 10 September 2004. It was commissioned by the Editorial Board and reflects the views of the author.
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