Chandelier Cells Research Articles

Characterization of axo‐axonic synapses in the piriform cortex of Mus musculus

Previous anatomical and physiological studies have established major glutamatergic and GABAergic neuronal subtypes within the piriform cortical circuits. However, quantitative information regarding axo-axonic inhibitory synapses mediated by chandelier cells across major cortical subdivisions of piriform cortex is lacking. Therefore, we examined the properties of these synapses across the entire piriform cortex. Our results show the following. 1) γ-Aminobutyric acid membrane transporter 1-positive varicosities, whose appearance resembles chandelier cartridges, are found around the initial segments of axons of glutamatergic cells across layers II and III. 2) Both the density of axo-axonic cartridges and the degree of γ-aminobutyric acid membrane transporter 1 innervation in each axo-axonic synapse are significantly higher in the piriform cortex than in the neocortex. 3) Glutamate decarboxylase 67, vesicular GABA transporter, and parvalbumin, but not calbindin, are colocalized with the presynaptic varicosities, whereas gephyrin, Na-K-2Cl cotransporter 1, and GABA(A) receptor α1 subunit, but not K-Cl cotransporter 2, are colocalized at the presumed postsynaptic sites. 4) The axo-axonic cartridges innervate the majority of excitatory neurons and are distributed more frequently in putative centrifugal cells and posterior piriform cortex. We further describe the morphology of chandelier cells by using parvalbumin-immunoreactivity and single-cell labeling. In summary, our results demonstrate that a small population of chandelier cells mediates abundant axo-axonic synapses across the entire piriform cortex. Because of the critical location of these inhibitory synapses in relation to action potential regulation, our results highlight a critical role of axo-axonic synapses in regulating information flow and olfactory-related oscillations within the piriform cortex in vivo.

State-Dependent Function of Neocortical Chandelier Cells

Chandelier (axoaxonic) cells (ChCs) are a distinct group of GABAergic interneurons that innervate the axon initial segments of pyramidal cells. However, their circuit role and the function of their clearly defined anatomical specificity remain unclear. Recent work has demonstrated that chandelier cells can produce depolarizing GABAergic PSPs, occasionally driving postsynaptic targets to spike. On the other hand, other work suggests that ChCs are hyperpolarizing and may have an inhibitory role. These disparate functional effects may reflect heterogeneity among ChCs. Here, using brain slices from transgenic mouse strains, we first demonstrate that, across different neocortical areas and genetic backgrounds, upper Layer 2/3 ChCs belong to a single electrophysiologically and morphologically defined population, extensively sampling Layer 1 inputs with asymmetric dendrites. Consistent with being a single cell type, we find electrical coupling between ChCs. We then investigate the effect of chandelier cell activation on pyramidal neuron spiking in several conditions, ranging from the resting membrane potential to stimuli designed to approximate in vivo membrane potential dynamics. We find that under quiescent conditions, chandelier cells are capable of both promoting and inhibiting spike generation, depending on the postsynaptic membrane potential. However, during in vivo-like membrane potential fluctuations, the dominant postsynaptic effect was a strong inhibition. Thus, neocortical chandelier cells, even from within a homogeneous population, appear to play a dual role in the circuit, helping to activate quiescent pyramidal neurons, while at the same time inhibiting active ones.

A Blueprint for the Spatiotemporal Origins of Mouse Hippocampal Interneuron Diversity

Although vastly outnumbered, inhibitory interneurons critically pace and synchronize excitatory principal cell populations to coordinate cortical information processing. Precision in this control relies upon a remarkable diversity of interneurons primarily determined during embryogenesis by genetic restriction of neuronal potential at the progenitor stage. Like their neocortical counterparts, hippocampal interneurons arise from medial and caudal ganglionic eminence (MGE and CGE) precursors. However, while studies of the early specification of neocortical interneurons are rapidly advancing, similar lineage analyses of hippocampal interneurons have lagged. A "hippocampocentric" investigation is necessary as several hippocampal interneuron subtypes remain poorly represented in the neocortical literature. Thus, we investigated the spatiotemporal origins of hippocampal interneurons using transgenic mice that specifically report MGE- and CGE-derived interneurons either constitutively or inducibly. We found that hippocampal interneurons are produced in two neurogenic waves between E9-E12 and E12-E16 from MGE and CGE, respectively, and invade the hippocampus by E14. In the mature hippocampus, CGE-derived interneurons primarily localize to superficial layers in strata lacunosum moleculare and deep radiatum, while MGE-derived interneurons readily populate all layers with preference for strata pyramidale and oriens. Combined molecular, anatomical, and electrophysiological interrogation of MGE/CGE-derived interneurons revealed that MGE produces parvalbumin-, somatostatin-, and nitric oxide synthase-expressing interneurons including fast-spiking basket, bistratified, axo-axonic, oriens-lacunosum moleculare, neurogliaform, and ivy cells. In contrast, CGE-derived interneurons contain cholecystokinin, calretinin, vasoactive intestinal peptide, and reelin including non-fast-spiking basket, Schaffer collateral-associated, mossy fiber-associated, trilaminar, and additional neurogliaform cells. Our findings provide a basic blueprint of the developmental origins of hippocampal interneuron diversity.

Interaction of inhibition and synaptic plasticity in a model of the hippocampal CA1 microcircuit

Cellular activity in the CA1 area of the hippocampus waxes and wanes at theta frequency (4-7Hz) when a rat is exploring an environment. Perisomatic inhibition onto pyramidal cells from basket cells and axoaxonic cells tends to be strongest out of phase with pyramidal cell activity, in a so-called storage cycle, whereas dendritic inhibition, mediated by bistratified and oriens lacunosum-moleculare (OLM) cells is strongest in phase with pyramidal cell activity [1], in a so-called recall cycle. Synaptic plasticity also varies across the theta cycle, from strong LTP to LTD, putatively corresponding to the storage and recall cycles for information patterns encoded in pyramidal cell activity [2]. The mechanisms underpinning the phasic changes in plasticity are not clear, but it is likely that inhibition plays a role by affecting levels of electrical activity and calcium levels at synapses. Calcium levels at dendritic synapses could reach the amplitudes required for LTP when inhibition is restricted to the perisomatic region, but may be restricted to amplitudes that result in LTD when inhibition is strong in the dendrites. We explore this hypothesis using a detailed multicompartmental model of a CA1 pyramidal cell [3] which is driven by spatially-focused patterns of excitation and inhibition. We employ a model of the CA1 microcircuit [4] that also includes basket, axoaxonic, bistratified and OLM cells and inputs from the entorhinal cortex (EC), the CA3 Schaffer collaterals and medial septum. A trigger of synaptic modifications, the intracellular calcium concentration, is modeled in a spine that expresses AMPA/NMDA-receptor-mediated synaptic responses and is located on a stratum radiatum (SR) dendrite of the CA1 pyramidal cell. The resulting calcium signals are used in a model of spike-timing-dependent synaptic plasticity [5] to predict the synaptic modifications across the theta cycle. We show that in the storage cycle, EC input-induced dendritic spikes propagate from the stratum lacunosum moleculare (SLM) dendrites to the SR dendritic regions in the CA1 pyramidal cell, coincide with the CA3 inputs, induce large calcium influx into the spine on the SR dendrite and cause LTP [6]. In the recall cycle, dendritic inhibition provided by bistratified and OLM cells prevents dendritic spike propagation into the SR region, restricts calcium increase and results in LTD induction. Removing dendritic inhibition in recall cycles allows dendritic spikes reaching SR dendrites and reverts LTD to LTP. The results suggest that dendritic inhibition acts as a switch that prevents LTP and promotes LTD during the recall memories and in forgetting no longer relevant memories.

The Cell Adhesion Molecule Neurofascin Stabilizes Axo-axonic GABAergic Terminals at the Axon Initial Segment

Cell adhesion molecules regulate synapse formation and maintenance via transsynaptic contact stabilization involving both extracellular interactions and intracellular postsynaptic scaffold assembly. The cell adhesion molecule neurofascin is localized at the axon initial segment of granular cells in rat dentate gyrus, which is mainly targeted by chandelier cells. Lentiviral shRNA-mediated knockdown of neurofascin in adult rat brain indicates that neurofascin regulates the number and size of postsynaptic gephyrin scaffolds, the number of GABA(A) receptor clusters as well as presynaptic glutamate decarboxylase-positive terminals at the axon initial segment. By contrast, overexpression of neurofascin in hippocampal neurons increases gephyrin cluster size presumably via stimulation of fibroblast growth factor receptor 1 signaling pathways.

Spatial and Temporal Bias in the Mitotic Origins of Somatostatin- and Parvalbumin-Expressing Interneuron Subgroups and the Chandelier Subtype in the Medial Ganglionic Eminence

GABAergic interneurons modulate cortical activity through the actions of distinct subgroups. Recent studies using interneuron transplants have shown tremendous promise as cell-based therapies for seizure disorders, Parkinson's disease, and in the study of neocortical plasticity. Previous reports identified a spatial bias for the origins of parvalbumin (PV)- and somatostatin (SST)-expressing interneuron subgroups within the medial ganglionic eminence (MGE). In the current study, the mitotic origins of these interneurons are examined by harvesting MGE cells at 2 time points and evaluating their neurochemical profiles after transplantation into neonatal mouse cortex. Although the dorsal MGE (dMGE)-SST and ventral MGE (vMGE)-PV bias were confirmed, both subgroups originate from progenitors located throughout the MGE. The dMGE bias was also found for SST subgroups that coexpress calretinin or reelin. In contrast, another major subgroup of SST interneuron, neuropeptide Y-expressing, does not appear to originate within the MGE. Finally, novel evidence is provided that a clinically important subtype of PV-expressing interneuron, the chandelier (axo-axonic) cell, is greatly enriched in transplants from the vMGE at embryonic day 15. These findings have important implications both for the study of interneuron fate determination and for studies that use interneuron precursor transplantation to alter cortical activity.

Reply: Impaired mitochondrial function abolishes gamma oscillations in the hippocampus through an effect on fast-spiking interneurons

ARTICLE Sir, We appreciate the letter of Whittaker et al . (2011) who report on the effects of metabolic stress on the properties of excitatory pyramidal cells and fast-spiking inhibitory interneurons during gamma oscillations. The authors combined extra- and intracellular electrophysiological recordings and pharmacology in rat hippocampal slices in vitro . Gamma oscillations are generally thought to represent a temporal matrix of higher brain functions and have been observed in all cortical brain structures, including the hippocampus (Bartos et al. , 2007; Uhlhaas and Singer, 2010; Whittington et al. , 2011). In hippocampal neuronal networks, the precise interaction of several types of inhibitory GABAergic interneurons (releasing neurotransmitter, γ-aminobutyric acid) and excitatory pyramidal cells is essential for the establishment of gamma oscillations. Inhibitory GABAergic interneurons are characterized by much higher action potential firing rates than excitatory pyramidal cells (Hajos et al. , 2009). Highly active inhibitory interneurons are the axo-axonic cells and the parvalbumin-containing basket cells that have been reported to generate action potentials at ∼40 Hz during gamma oscillations or at ∼200 Hz during sharp-wave ripple activity (Ylinen et al. , 1995; Penttonen et al. , 1998; Klausberger et al. , 2003). In many in vitro studies, gamma oscillations have been induced in hippocampal slice preparations by bath application of cholinergic receptor agonists (acetylcholine or carbachol; cholinergic model) or glutamatergic receptor agonist, kainic …

Prefrontal cortical network connections: key site of vulnerability in stress and schizophrenia

The symptoms of schizophrenia involve profound dysfunction of the prefrontal cortex (PFC). PFC networks create our “mental sketch pad”, and PFC dysfunction contributes to symptoms such as cognitive deficits, thought disorder, delusions and hallucinations. Neuropathological studies of schizophrenia have shown marked loss of dendritic spines in deep layer III, the sublayer where PFC microcircuits reside. The microcircuits consist of recurrent excitatory pyramidal cell networks that interconnect on spines, and excite each other via NMDA receptor signaling. The pyramidal cell persistent firing is sculpted by lateral inhibition from GABAergic basket and chandelier cells, thus creating tuned, persistent firing needed for accurate representational knowledge (i.e., working memory). The strength of pyramidal cell network connections is markedly and flexibly altered by intracellular signaling pathways in dendritic spines, a process called dynamic network connectivity (DNC). DNC proteins such as HCN channels are concentrated on dendritic spines in deep layer III. Under optimal conditions, network inputs to pyramidal cells are strengthened by noradrenergic alpha-2A inhibition of cAMP–HCN channel signaling, and sculpted by dopamine D1-cAMP–HCN channel weakening of inappropriate inputs. However, with stress exposure, high levels of cAMP–HCN channel signaling produces a collapse in network firing. With chronic stress exposure, spines reduce in size and are lost, and this process involves increased PKC signaling. Importantly, molecules that normally strengthen PFC networks connections and/or reverse the stress response, are often genetically altered in schizophrenia. As exposure to stress is a key factor in the precipitation of schizophrenic symptoms, these dysregulated signaling pathways in deep layer III may interact with already vulnerable circuitry to cause spine loss and the descent into illness.

Pharmacological Enhancement of Cognition in Individuals with Schizophrenia

w n “ i fi a f n d c t o t t T he principal pharmacological treatment for schizophrenia, antipsychotic medications, reduces the severity of positive symptoms but has little or no effect on the cognitive impairents that are the major determinants of long-term social and ccupational outcome. In addition to their limited effectiveness, all edications currently used to treat schizophrenia are derivative of erendipitous discoveries over a half century ago. These problems mphasize the need for a new approach to developing pharmacoogical interventions in schizophrenia that begins with the identifiation of molecular targets on the basis of their role in the pathohysiology of an illness (1). One such target, 2 subunit-containing -aminobutyric acid-A (GABAA) receptors, is the subject of a randomized clinical trial conducted by Buchanan et al. (2) through the National Institute of Mental Health–funded Treatment Units for Research on Neurocognition in Schizophrenia Network and reported in this issue of Biological Psychiatry. The rationale for the study derives from the following hypothesis: increased levels of GABAA receptor 2 subunit protein and mesenger RNA in the dorsolateral prefrontal cortex of subjects with chizophrenia represent a compensatory response to deficient ABA synthesis in the chandelier subclass of parvalbumin-expressng GABA neurons that signal to postsynaptic pyramidal neurons ia 2-containing GABAA receptors (3). Thus, enhancing this signaling with a drug that selectively activates 2-containing GABAA receptors and that does so only when GABA is normally released from presynaptic chandelier neurons would augment the intrinsic compensatory response and improve the function of the affected neural network. Specifically, positive modulation of 2-containing GABAA receptors was predicted: 1) to increase the power of the frontal lobe band (30 – 80 Hz) oscillations that are impaired in schizophrenia (4), and 2) to improve performance on these tasks because working memory and related cognitive control tasks seem to be dependent on oscillations (5). Preclinical studies demonstrated, consistent with this hypothesis, that compounds with relatively selective agonist activity for 2-containing GABAA receptors improved working memory (6) and increased oscillations (7) in pharmacological models of schizophrenia in monkeys and mice, respectively. In healthy human volunteers, TPA023 (a.k.a. MK-0777), a relatively selective positive modulator of GABAA receptors containing 2 or 3 subunits, had a cognitive-sparing profile compared with typical benzodiazepines, which are nonselective positive modulators of GABAA receptors ontaining 1, 2, 3, or 5 subunits (8). Finally, in a small, proof-ofconcept, randomized clinical trial, subjects with schizophrenia treated with MK-0777 showed increased frontal oscillations and improved performance on several working memory tasks, including the AX-type continuous performance test and N-Back, relative to subjects receiving placebo (9). In contrast, in the larger, multisite, randomized clinical trial conducted by Buchanan et al., subjects

Cholinergic control of GABA release by carbachol at perisomatic inhibitory synapses in the CA3 region of mouse hippocampus

Event Abstract Back to Event Cholinergic control of GABA release by carbachol at perisomatic inhibitory synapses in the CA3 region of mouse hippocampus G. G. Szabó1, N. Holderith1, A. I. Gulyás1, T. F. Freund1 and N. Hájos1* 1 Hungarian Academy of Sciences, Institute of Experimental Medicine, Hungary Action potential generation of hippocampal pyramidal neurons is controlled by perisomatic inhibition, originating from fast-spiking basket (FSBC)- and axo-axonic cells (AACs) as well as from regular spiking basket cells (RSBCs). These neurons play a role in feedforward and feedback inhibition and are tuned by cholinergic receptor activation. We aimed to clarify the impact of cholinergic receptor activation on synaptic communication between these perisomatic inhibitory neurons (PINs) and pyramidal cells (PCs). By performing paired recordings between the three types of PINs and PCs in mouse hippocampal slices, we investigated the release properties and their sensitivity to the cholinergic receptor agonist carbachol (CCh). Synaptic currents originating from the distinct types of PINs had different properties recorded in CA3 PCs. Analyzes of the decay kinetics suggested that at AAC-PC pairs synaptic cross-talk may occur between adjacent release sites. RSBCs showed robust asynchronous release, whereas the other two types of PINs did not. CCh decreased the GABA release significantly from all the three types of PINs to a different extent and via different receptor activation. In addition, CCh significantly reduced the short-term depression of synaptic transmission at FSBC- and AAC-PC pairs.These findings suggest that the contribution of different types of PINs to feedforward and feedback inhibition might be distinct that could be altered by cholinergic receptor activation. Keywords: Neurophysiology, Neuroscience Conference: 13th Conference of the Hungarian Neuroscience Society (MITT), Budapest, Hungary, 20 Jan - 22 Jan, 2011. Presentation Type: Abstract Topic: Neurophysiology Citation: Szabó GG, Holderith N, Gulyás AI, Freund TF and Hájos N (2011). Cholinergic control of GABA release by carbachol at perisomatic inhibitory synapses in the CA3 region of mouse hippocampus. Front. Neurosci. Conference Abstract: 13th Conference of the Hungarian Neuroscience Society (MITT). doi: 10.3389/conf.fnins.2011.84.00038 Copyright: The abstracts in this collection have not been subject to any Frontiers peer review or checks, and are not endorsed by Frontiers. They are made available through the Frontiers publishing platform as a service to conference organizers and presenters. The copyright in the individual abstracts is owned by the author of each abstract or his/her employer unless otherwise stated. Each abstract, as well as the collection of abstracts, are published under a Creative Commons CC-BY 4.0 (attribution) licence (https://creativecommons.org/licenses/by/4.0/) and may thus be reproduced, translated, adapted and be the subject of derivative works provided the authors and Frontiers are attributed. For Frontiers’ terms and conditions please see https://www.frontiersin.org/legal/terms-and-conditions. Received: 03 Mar 2011; Published Online: 23 Mar 2011. * Correspondence: Dr. N. Hájos, Hungarian Academy of Sciences, Institute of Experimental Medicine, Budapest, Hungary, hajos@koki.hu Login Required This action requires you to be registered with Frontiers and logged in. To register or login click here. Abstract Info Abstract The Authors in Frontiers G. G Szabó N. Holderith A. I Gulyás T. F Freund N. Hájos Google G. G Szabó N. Holderith A. I Gulyás T. F Freund N. Hájos Google Scholar G. G Szabó N. Holderith A. I Gulyás T. F Freund N. Hájos PubMed G. G Szabó N. Holderith A. I Gulyás T. F Freund N. Hájos Related Article in Frontiers Google Scholar PubMed Abstract Close Back to top Javascript is disabled. Please enable Javascript in your browser settings in order to see all the content on this page.

Output specificity of GABAergic interneurons in the rat somatosensory cortex

Event Abstract Back to Event Output specificity of GABAergic interneurons in the rat somatosensory cortex E. Vámos1, J. Baka1, M. Rózsa1, G. Komlósi1, S. Oláh1*, G. Molnár1, J. Szabadics1 and G. Tamás1 1 University of Szeged, Department of Physiology, Anatomy and Neuroscience, Hungary The output of GABAergic cells in the cerebral cortex is distributed among pyramidal cells and interneurons and distinct interneuron types evolved to form connections selectively with pyramidal cells and GABAergic cells. We tested 13087 connections between simultaneously whole cell patch clamp recorded neurons recorded during the last 12 years in supragranular layers of the somatosensory cortex of the rat (P18-35). This database yielded 2632 monosynaptic connections involving 4956 neurons. Based on firing and morphological characteristics, we classified the recorded neurons into the following 7 populations: pyramidal cells, neurogliaform cells, Martinotti cells, basket cells, regular spiking cells, axo-axonic cells and irregular spiking cells. Most types of interneurons innervated both pyramidal and GABAergic cells, but axo-axonic cells provided output selectively to pyramidal neurons. In addition, we found that irregular spiking cells innervated GABAergic interneurons exclusively (25 postsynaptic interneurons out of 175 tested), none of the simultaneously recorded pyramidal cells (n=237) received input from irregular spiking cells (chi2 <0.0001). We found no sign of morphological heterogeneity among irregular spiking cells which were characterized by a narrow columnar axonal pattern. In conclusion, apart from confirming interneuron types with mixed and pyramidal cell specific output, we identified a homogeneous interneuron population which selectively innervates GABAergic cells in supragranular layers of the somatosensory cortex. Keywords: Neurophysiology, Neuroscience Conference: 13th Conference of the Hungarian Neuroscience Society (MITT), Budapest, Hungary, 20 Jan - 22 Jan, 2011. Presentation Type: Abstract Topic: Neurophysiology Citation: Vámos E, Baka J, Rózsa M, Komlósi G, Oláh S, Molnár G, Szabadics J and Tamás G (2011). Output specificity of GABAergic interneurons in the rat somatosensory cortex. Front. Neurosci. Conference Abstract: 13th Conference of the Hungarian Neuroscience Society (MITT). doi: 10.3389/conf.fnins.2011.84.00064 Copyright: The abstracts in this collection have not been subject to any Frontiers peer review or checks, and are not endorsed by Frontiers. They are made available through the Frontiers publishing platform as a service to conference organizers and presenters. The copyright in the individual abstracts is owned by the author of each abstract or his/her employer unless otherwise stated. Each abstract, as well as the collection of abstracts, are published under a Creative Commons CC-BY 4.0 (attribution) licence (https://creativecommons.org/licenses/by/4.0/) and may thus be reproduced, translated, adapted and be the subject of derivative works provided the authors and Frontiers are attributed. For Frontiers’ terms and conditions please see https://www.frontiersin.org/legal/terms-and-conditions. Received: 03 Mar 2011; Published Online: 23 Mar 2011. * Correspondence: Dr. S. Oláh, University of Szeged, Department of Physiology, Anatomy and Neuroscience, Szeged, Hungary, olah.zita87@gmail.com Login Required This action requires you to be registered with Frontiers and logged in. To register or login click here. Abstract Info Abstract The Authors in Frontiers E. Vámos J. Baka M. Rózsa G. Komlósi S. Oláh G. Molnár J. Szabadics G. Tamás Google E. Vámos J. Baka M. Rózsa G. Komlósi S. Oláh G. Molnár J. Szabadics G. Tamás Google Scholar E. Vámos J. Baka M. Rózsa G. Komlósi S. Oláh G. Molnár J. Szabadics G. Tamás PubMed E. Vámos J. Baka M. Rózsa G. Komlósi S. Oláh G. Molnár J. Szabadics G. Tamás Related Article in Frontiers Google Scholar PubMed Abstract Close Back to top Javascript is disabled. Please enable Javascript in your browser settings in order to see all the content on this page.

The chandelier neuron in schizophrenia

Markers of GABA neurotransmission between chandelier neurons and their synaptic targets, the axon initial segment (AIS) of pyramidal neurons, are altered in the dorsolateral prefrontal cortex (DLPFC) of subjects with schizophrenia. For example, immunoreactivity for the GABA membrane transporter (GAT1) is decreased in presynaptic chandelier neuron axon terminals, whereas immunoreactivity for the GABA(A) receptor α2 subunit is increased in postsynaptic AIS. These alterations are most marked in cortical layers 2-3. In addition, other determinants of the function of chandelier cell-pyramidal neuron synapses, such as ankyrin-G (which regulates the recruitment of sodium channels to the AIS), are also selectively altered in superficial layer pyramidal neurons in subjects with schizophrenia. Each of these components of chandelier cell-pyramidal neuron connectivity exhibits distinctive developmental trajectories in the primate DLPFC, suggesting that disturbances in these trajectories could contribute to the pathogenesis of schizophrenia. Recent findings that inputs from neocortical chandelier neurons are excitatory provide new ideas about the role of this circuitry in the pathophysiology of cortical dysfunction in schizophrenia.

Three groups of interneurons account for nearly 100% of neocortical GABAergic neurons

An understanding of the diversity of cortical GABAergic interneurons is critical to understand the function of the cerebral cortex. Recent data suggest that neurons expressing three markers, the Ca2+-binding protein parvalbumin (PV), the neuropeptide somatostatin (SST), and the ionotropic serotonin receptor 5HT3a (5HT3aR) account for nearly 100% of neocortical interneurons. Interneurons expressing each of these markers have a different embryological origin. Each group includes several types of interneurons that differ in morphological and electrophysiological properties and likely have different functions in the cortical circuit. The PV group accounts for ∼40% of GABAergic neurons and includes fast spiking basket cells and chandelier cells. The SST group, which represents ∼30% of GABAergic neurons, includes the Martinotti cells and a set of neurons that specifically target layerIV. The 5HT3aR group, which also accounts for ∼30% of the total interneuronal population, is heterogeneous and includes all of the neurons that express the neuropeptide VIP, as well as an equally numerous subgroup of neurons that do not express VIP and includes neurogliaform cells. The universal modulation of these neurons by serotonin and acetylcholine via ionotropic receptors suggests that they might be involved in shaping cortical circuits during specific brain states and behavioral contexts.

Temporal Dynamics of Distinct CA1 Cell Populations during Unconscious State Induced by Ketamine

Ketamine is a widely used dissociative anesthetic which can induce some psychotic-like symptoms and memory deficits in some patients during the post-operative period. To understand its effects on neural population dynamics in the brain, we employed large-scale in vivo ensemble recording techniques to monitor the activity patterns of simultaneously recorded hippocampal CA1 pyramidal cells and various interneurons during several conscious and unconscious states such as awake rest, running, slow wave sleep, and ketamine-induced anesthesia. Our analyses reveal that ketamine induces distinct oscillatory dynamics not only in pyramidal cells but also in at least seven different types of CA1 interneurons including putative basket cells, chandelier cells, bistratified cells, and O-LM cells. These emergent unique oscillatory dynamics may very well reflect the intrinsic temporal relationships within the CA1 circuit. It is conceivable that systematic characterization of network dynamics may eventually lead to better understanding of how ketamine induces unconsciousness and consequently alters the conscious mind.

Hippocampal spatial navigation: interneurons take responsibility

Hippocampal spatial navigation: interneurons take responsibility

Parvalbumin-Containing Fast-Spiking Basket Cells Generate the Field Potential Oscillations Induced by Cholinergic Receptor Activation in the Hippocampus

Gamma frequency oscillations in cortical regions can be recorded during cognitive processes, including attention or memory tasks. These oscillations are generated locally as a result of reciprocal interactions between excitatory pyramidal cells and perisomatic inhibitory interneurons. Here, we examined the contribution of the three perisomatic interneuron types--the parvalbumin-containing fast-spiking basket cells (FSBCs) and axo-axonic cells (AACs), as well as the cholecystokinin-containing regular-spiking basket cells (RSBCs) to cholinergically induced oscillations in hippocampal slices, a rhythmic activity that captures several features of the gamma oscillations recorded in vivo. By analyzing the spiking activities of single neurons recorded in parallel with local field potentials, we found that all three cell types fired phase locked to the carbachol-induced oscillations, although with different frequencies and precision. During these oscillations, FSBCs fired the most with the highest accuracy compared with the discharge of AACs and RSBCs. In further experiments, we showed that activation of μ-opioid receptors by DAMGO ([D-Ala(2),N-Me-Phe(4),Gly(5)-ol]enkephalin acetate), which significantly reduced the inhibitory, but not excitatory, transmission, suppressed or even blocked network oscillations both in vitro and in vivo, leading to the desynchronization of pyramidal cell firing. Using paired recordings, we demonstrated that carbachol application blocked GABA release from RSBCs and reduced it from FSBCs and AACs, whereas DAMGO further suppressed the GABA release only from FSBCs, but not from AACs. These results collectively suggest that the rhythmic perisomatic inhibition, generating oscillatory fluctuation in local field potentials after carbachol treatment of hippocampal slices, is the result of periodic GABA release from FSBCs.

Prototypic Seizure Activity Driven by Mature Hippocampal Fast-Spiking Interneurons

A variety of epileptic seizure models have shown that activation of glutamatergic pyramidal cells is usually required for rhythm generation and/or synchronization in hippocampal seizure-like oscillations in vitro. However, it still remains unclear whether GABAergic interneurons may be able to drive the seizure-like oscillations without glutamatergic transmission. Here, we found that electrical stimulation in rat hippocampal CA1 slices induced a putative prototype of seizure-like oscillations ("prototypic afterdischarge," 1.8-3.8 Hz) in mature pyramidal cells and interneurons in the presence of ionotropic glutamate receptor antagonists. The prototypic afterdischarge was abolished by GABA(A) receptor antagonists or gap junction blockers, but not by a metabotropic glutamate receptor antagonist or a GABA(B) receptor antagonist. Gramicidin-perforated patch-clamp and voltage-clamp recordings revealed that pyramidal cells were depolarized and frequently excited directly through excitatory GABAergic transmissions in each cycle of the prototypic afterdischarge. Interneurons that were actively spiking during the prototypic afterdischarge were mostly fast-spiking (FS) interneurons located in the strata oriens and pyramidale. Morphologically, these interneurons that might be "potential seizure drivers" included basket, chandelier, and bistratified cells. Furthermore, they received direct excitatory GABAergic input during the prototypic afterdischarge. The O-LM cells and most of the interneurons in the strata radiatum and lacunosum moleculare were not essential for the generation of prototypic afterdischarge. The GABA-mediated prototypic afterdischarge was observed later than the third postnatal week in the rat hippocampus. Our results suggest that an FS interneuron network alone can drive the prototypic form of electrically induced seizure-like oscillations through their excitatory GABAergic transmissions and presumably through gap junction-mediated communications.

D2 and D4 dopamine receptor mRNA distribution in pyramidal neurons and GABAergic subpopulations in monkey prefrontal cortex: implications for schizophrenia treatment

D2 and D4 dopamine receptors play an important role in cognitive functions in the prefrontal cortex and they are involved in the pathophysiology of neuropsychiatric disorders such as schizophrenia. The eventual effect of dopamine upon pyramidal neurons in the prefrontal cortex depends on which receptors are expressed in the different neuronal populations. Parvalbumin and calbindin mark two subpopulations of cortical GABAergic interneurons that differently innervate pyramidal cells. Recent hypotheses about schizophrenia hold that the root of the illness is a dysfunction of parvalbumin chandelier cells that produces disinhibition of pyramidal cells. In the present work we report double in situ hybridization histochemistry experiments to determine the prevalence of D2 receptor mRNA and D4 receptor mRNA in glutamatergic neurons, GABAergic interneurons and both parvalbumin and calbindin GABAergic subpopulations in monkey prefrontal cortex layer V. We found that around 54% of glutamatergic neurons express D2 mRNA and 75% express D4 mRNA, while GAD-positive interneurons express around 34% and 47% respectively. Parvalbumin cells mainly expressed D4 mRNA (65%) and less D2 mRNA (15–20%). Finally, calbindin cells expressed both receptors in similar proportions (37%). We hypothesized that D4 receptor could be a complementary target in designing new antipsychotics, mainly because of its predominance in parvalbumin interneurons.

Neocortical Interneurons: From Diversity, Strength

Interneurons in the neocortex of the brain are small, locally projecting inhibitory GABAergic cells with a broad array of anatomical and physiological properties. The diversity of interneurons is believed to be crucial for regulating myriad operations in the neocortex. Here, we describe current theories about how interneuron diversity may support distinct neocortical processes that underlie perception.

Network dynamics of encoding and retrieval of behavioural spike sequences during theta and ripples in a CA1 model of the hippocampus

Spatial memory in the hippocampus is encoded and retrieved by the firing frequency and spike timing of pyramidal cells and inhibitory interneurons during network oscillations. Theta oscillations (4-10 Hz) are observed in rats during exploration and rapid eye movement (REM) sleep, whereas sharp wave-associated ripples (100-200 Hz) are observed during slow-wave sleep (SWS) and consummatory behaviours. Hippocampal theta rhythm has been suggested to contribute to memory formation by separating encoding and retrieval into functional sub-cycles [1]. On the other hand, ripple activity has been demonstrated to structure temporally compressed forward and reverse replay of waking neuronal activity [2-4]. Recent experimental studies have shown that different CA1 excitatory and inhibitory neurons fire at different phases of the theta and ripple rhythms [5-7]. Similarly, medial septal GABAergic neurons differentially phase their activities with respect to theta and ripple [8,9]. We investigate, via computer simulations, the biophysical mechanisms by which storage and recall of behavioural spike sequences are achieved by the CA1 microcircuitry. A model of the CA1 microcircuit [10-12] is extended that uses biophysical representations of the major cell types, including pyramidal (P) cells and five types of inhibitory interneurons: basket (B) cells, axo-axonic (AA) cells, bistratified (BS) cells, IVY cells and oriens lacunosum-moleculare (OLM) cells. Inputs to the network come from the entorhinal cortex (EC), the CA3 Schaffer collaterals and medial septum. Our model addresses two important issues: (1) How are encoding and replay (forward and reverse) of behavioural place sequences controlled in the CA1 microcircuit during theta and ripples? (2) What roles do the various types of inhibitory interneurons play in these encoding and retrieval processes?