Perisomatic Region Research Articles

Polysialic acid is required for dopamine D2 receptor-mediated plasticity involving inhibitory circuits of the rat medial prefrontal cortex.

Decreased expression of dopamine D2 receptors (D2R), dysfunction of inhibitory neurotransmission and impairments in the structure and connectivity of neurons in the medial prefrontal cortex (mPFC) are involved in the pathogenesis of schizophrenia and major depression, but the relationship between these changes remains unclear. The polysialylated form of the neural cell adhesion molecule (PSA-NCAM), a plasticity-related molecule, may serve as a link. This molecule is expressed in cortical interneurons and dopamine, via D2R, modulates its expression in parallel to that of proteins related to synapses and inhibitory neurotransmission, suggesting that D2R-targeted antipsychotics/antidepressants may act by affecting the plasticity of mPFC inhibitory circuits. To understand the role of PSA-NCAM in this plasticity, rats were chronically treated with a D2R agonist (PPHT) after cortical PSA depletion. PPHT-induced increases in GAD67 and synaptophysin (SYN) neuropil expression were blocked when PSA was previously removed, indicating a role for PSA-NCAM in this plasticity. The number of PSA-NCAM expressing interneuron somata also increased after PPHT treatment, but the percentages of these cells belonging to different interneuronal subpopulations did not change. Cortical pyramidal neurons did not express PSA-NCAM, but puncta co-expressing this molecule and parvalbumin could be found surrounding their somata. PPHT treatment increased the number of PSA-NCAM and parvalbumin expressing perisomatic puncta, but decreased the percentage of parvalbumin puncta that co-expressed SYN. PSA depletion did not block these effects on the perisomatic region, but increased further the number of parvalbumin expressing puncta and increased the percentage of puncta co-expressing SYN and parvalbumin, suggesting that the polysialylation of NCAM may regulate perisomatic inhibition of mPFC principal neurons. Summarizing, the present results indicate that dopamine acting on D2R influences structural plasticity of mPFC interneurons and point to PSA-NCAM as a key player in this remodeling.

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.

Postsynaptic Group II Metabotropic Glutamate Receptor activation in Dentate Gyrus Granule Cells

Event Abstract Back to Event Postsynaptic Group II Metabotropic Glutamate Receptor activation in Dentate Gyrus Granule Cells J. Brunner1*, T. Andrási1, S. Van-Weert1, F. K. Borgmann2, S. Jessberger2 and J. Szabadics1 1 Hungarian Academy of Sciences, Institute of Experimental Medicine, Hungary 2 Swiss Federal Institute of Technology, Institute of Cell Biology, Switzerland Dentate gyrus granule cells (DGGCs) express group II metabotropic glutamate receptors (mGluR2/3) both on their axonal and somatodendritic membranes. Activation of axonal mGluR2/3s suppress the synaptic transmission from DGGCs due to down regulation of presynaptic Ca2+ channel activity. However, the function of dendritic mGluR2/3s in DGGCs is not known. First, we showed that bath application of mGluR2/3 selective agonists (DCG IV, APDC) resulted in significant, long-lasting hyperpolarization in DGGCs and this effect persisted in the presence of TTX but it was prevented by selective antagonists (APICA, LY 341495). DCG IV did not have any effect on the axonal membrane potential of DGGCs indicating distinct somatic and axonal mGluR2/3 mediated mechanisms. The hyperpolarizing DCG IV effect was absent in GABAergic and CA3 pyramidal cells. We also showed that the mGluR2/3 activation induced somatodendritic hyperpolarization was mediated by GIRK channels as intracellular GDPβS and bath application of inward-rectifier potassium channel blocker, tertiapin-Q occluded the DCG IV effect. Lastly, focal glutamate release by photolysis of MNI-glutamate in the perisomatic region of DGGCs resulted in mGluR2/3 mediated currents; however, similar current could be evoked in the dendritic region (>15 µm) suggesting that mGluR2/3 are activated by a specific glutamatergic source which innervates the perisomatic region of DGGCs and elicit mGluR2/3 mediated glutamatergic inhibition. 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: Brunner J, Andrási T, Van-Weert S, Borgmann FK, Jessberger S and Szabadics J (2011). Postsynaptic Group II Metabotropic Glutamate Receptor activation in Dentate Gyrus Granule Cells. Front. Neurosci. Conference Abstract: 13th Conference of the Hungarian Neuroscience Society (MITT). doi: 10.3389/conf.fnins.2011.84.00100 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. J. Brunner, Hungarian Academy of Sciences, Institute of Experimental Medicine, Budapest, Hungary, brunner.janos@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 J. Brunner T. Andrási S. Van-Weert F. K Borgmann S. Jessberger J. Szabadics Google J. Brunner T. Andrási S. Van-Weert F. K Borgmann S. Jessberger J. Szabadics Google Scholar J. Brunner T. Andrási S. Van-Weert F. K Borgmann S. Jessberger J. Szabadics PubMed J. Brunner T. Andrási S. Van-Weert F. K Borgmann S. Jessberger J. Szabadics 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.

Regulation of fast-spiking basket cell synapses by the chloride channel ClC-2

Parvalbumin-expressing, fast-spiking basket cells play key roles in the generation of synchronous, rhythmic population activities in the hippocampus. Here we show that GABAA receptor-mediated synaptic inputs from murine parvalbumin-expressing basket cells are selectively modulated by the membrane voltage- and intracellular chloride-dependent chloride channel ClC–2. These data demonstrate a novel cell type-specific regulation of intracellular chloride homeostasis in the perisomatic region of hippocampal pyramidal neurons.

Relationship of cannabinoid CB1 receptor and cholecystokinin immunoreactivity in monkey dorsolateral prefrontal cortex

Exposure to cannabis impairs cognitive functions reliant on the circuitry of the dorsolateral prefrontal cortex (DLPFC) and increases the risk of schizophrenia. The actions of cannabis are mediated via the brain cannabinoid 1 receptor (CB1R), which in rodents is heavily localized to the axon terminals of cortical GABA basket neurons that contain cholecystokinin (CCK). Differences in the laminar distribution of CB1R-immunoreactive (IR) axons have been reported between rodent and monkey neocortex, suggesting that the cell type(s) containing CB1Rs, and the synaptic targets of CB1R-IR axon terminals, may differ across species; however, neither the relationship of CB1Rs to CCK-containing interneurons, nor the postsynaptic targets of CB1R and CCK axon terminals, have been examined in primate DLPFC. Consequently, we compared the distribution patterns of CB1R- and CCK-IR structures, determined the proportions of CB1R and CCK neurons that were dual-labeled, and identified the synaptic types and postsynaptic targets of CB1R- and CCK-IR axon terminals in macaque monkey DLPFC. By light microscopy, CB1R- and CCK-IR axons exhibited a similar laminar distribution, with their greatest densities in layer 4. Dual-label fluorescence experiments demonstrated that 91% of CB1R-IR neurons were immunopositive for CCK, whereas only 51% of CCK-IR neurons were immunopositive for CB1R. By electron microscopy, all synapses formed by CB1R-IR axon terminals were symmetric, whereas CCK-IR axon terminals formed both symmetric (88%) and asymmetric (12%) synapses. The primary postsynaptic target of both CB1R- and CCK-IR axon terminals forming symmetric synapses was dendritic shafts (81–88%), with the remainder targeting cell bodies or dendritic spines. Thus, despite species differences in laminar distribution, CB1Rs are principally localized to CCK basket neuron axons in both rodent neocortex and monkey DLPFC. These axons target the perisomatic region of pyramidal neurons, providing a potential anatomical substrate for the impaired function of the DLPFC associated with cannabis use and schizophrenia.

Distinct Endocannabinoid Control of GABA Release at Perisomatic and Dendritic Synapses in the Hippocampus

Endocannabinoid-mediated retrograde synaptic signaling is a key regulator of GABA release at synapses formed on the perisomatic region of pyramidal cells by basket cells that coexpress the cannabinoid type 1 receptor (CB(1)R) and cholecystokinin (CCK). However, CB(1)R and CCK-positive GABAergic terminals are present on pyramidal cell dendrites as well, but the principles of endocannabinoid control of GABA release in dendrites are not understood. We performed paired recordings from CCK-positive perisomatically (basket cells) or dendritically projecting (Schaffer collateral-associated cells) interneurons and postsynaptic CA1 pyramidal cells to determine the properties of endocannabinoid signaling at GABAergic synapses along the somato-dendritic axis. Although several key elements of the currently known molecular machinery for endocannabinoid synthesis are thought be primarily localized in dendrites, our results revealed that the depolarization-induced suppression of inhibition, the endocannabinoid-mediated tonic inhibition of GABA release, and the metabotropic glutamate receptor activation-induced, CB(1)R-mediated depression of GABA release were all significantly less effective at dendritic compared with perisomatic synapses. In addition, low concentration of exogenous CB(1) receptor agonist inhibited GABA release to a lesser extent at dendritic compared with perisomatic synapses, indicating that presynaptic differences are partly responsible for the differential control of GABA release by endocannabinoids in dendrites. Together, these data demonstrate a novel domain-specific regulation of GABA release by endocannabinoid signaling in the hippocampus.

Diverse interneuron populations have highly specific interconnectivity in the rat piriform cortex

Previous studies have suggested that the patterns of innervation and high interconnectivity of the piriform cortex (PC) provide for strong olfactory hippocampal memory; however, these same attributes may create high seizurogenic tendencies. Thus, understanding this wiring is important from a physiological and pathophysiological perspective. Distinct interneurons expressing differing calcium binding proteins (CBPs), parvalbumin (PV), calbindin (CB), and calretinin (CR), have been shown to exist in PC. However, a comprehensive examination of the distribution and innervation patterns of these neurons has not been done. Thus the purpose of this study was to combine the analysis of the CBP cell localization with analysis of their innervation patterns. Each type was differentially localized in the three layers of the PC. Only CR-positive neurons were found in layer 1. PV and CB are coexpressed in layers 2-3, most expressing both PV and CB. A morphological estimate of the dendritic extent for each subtype showed that PV and PV/CB cells demonstrated equally wide, horizontal and vertical arborizations, whereas CB cells had wide horizontal and restricted vertical arborizations. CR cells had restricted horizontal and very long vertical arborizations. Postsynaptic morphological targeting was also found to be specific, namely, PV(+) and PV/CB(+) nerve terminals (NTs) innervate perisomatic regions of principal cells. CR(+) NTs innervate only dendrites of principal cells, and CB(+) NTs innervate both somata and dendrites of principal cells. These data show highly complex innervation patterns for all of the CBP interneurons of the PC and form a basis for further studies in the plasticity of this region.

Perisomatic Voltage-Gated Sodium Channels Actively Maintain Linear Synaptic Integration in Principal Neurons of the Medial Superior Olive

Principal neurons of the medial superior olive (MSO) compute azimuthal sound location by integrating phase-locked inputs from each ear. While previous experimental and modeling studies have proposed that voltage-gated sodium channels (VGSCs) play an important role in synaptic integration in the MSO, these studies appear at odds with the unusually weak active backpropagation of action potentials into the soma and dendrites. To understand the spatial localization and biophysical properties of VGSCs, we isolated sodium currents in MSO principal neurons in gerbil brainstem slices. Nucleated and cell-attached patches revealed that VGSC density at the soma is comparable to that of many other neuron types, but channel expression is largely absent from the dendrites. Further, while somatic VGSCs activated with conventional voltage dependence (V(1/2) = -30 mV), they exhibited an unusually negative range of steady-state inactivation (V(1/2) = -77 mV), leaving approximately 92% of VGSCs inactivated at the resting potential (approximately -58 mV). In current-clamp experiments, non-inactivated VGSCs were sufficient to amplify subthreshold EPSPs near action potential threshold, counterbalancing the suppression of EPSP peaks by low voltage-activated potassium channels. EPSP amplification was restricted to the perisomatic region of the neuron, and relatively insensitive to preceding inhibition. Finally, computational modeling showed that the exclusion of VGSCs from the dendrites equalizes somatic EPSP amplification across synaptic locations and lowered the threshold for bilateral versus unilateral excitatory synaptic inputs. Together, these findings suggest that the pattern of sodium channel expression in MSO neurons contributes to these neurons' selectivity for coincident binaural inputs.

Cell Type-Specific Long-Term Plasticity at Glutamatergic Synapses onto Hippocampal Interneurons Expressing either Parvalbumin or CB1Cannabinoid Receptor

Different GABAergic interneuron types have specific roles in hippocampal function, and anatomical as well as physiological features vary greatly between interneuron classes. Long-term plasticity of interneurons has mostly been studied in unidentified GABAergic cells and is known to be very heterogeneous. Here we tested whether cell type-specific plasticity properties in distinct GABAergic interneuron types might underlie this heterogeneity. We show that long-term potentiation (LTP) and depression (LTD), two common forms of synaptic plasticity, are expressed in a highly cell type-specific manner at glutamatergic synapses onto hippocampal GABAergic neurons. Both LTP and LTD are generated in interneurons expressing parvalbumin (PV+), whereas interneurons with similar axon distributions but expressing cannabinoid receptor-1 show no lasting plasticity in response to the same protocol. In addition, LTP or LTD occurs in PV+ interneurons with different efferent target domains. Perisomatic-targeting PV+ basket and axo-axonic interneurons express LTP, whereas glutamatergic synapses onto PV+ bistratified cells display LTD. Both LTP and LTD are pathway specific, independent of NMDA receptors, and occur at synapses with calcium-permeable (CP) AMPA receptors. Plasticity in interneurons with CP-AMPA receptors strongly modulates disynaptic GABAergic transmission onto CA1 pyramidal cells. We propose that long-term plasticity adjusts the synaptic strength between pyramidal cells and interneurons in a cell type-specific manner and, in the defined CA1 interneurons, shifts the spatial pattern of inhibitory weight from pyramidal cell dendrites to the perisomatic region.

How much inhibition in an epileptiform burst?

How much inhibition in an epileptiform burst?

Direct Action of two major Antidepressants on a Specific Inhibitory Circuit of the Hippocampus

Event Abstract Back to Event Direct Action of two major Antidepressants on a Specific Inhibitory Circuit of the Hippocampus A. Bacci1, P. Mendez1* and A. Pazienti1 1 European Brain Research Institute, Italy Hippocampal inhibitory synapses innervating the perisomatic region of principal pyramidal neurons originate from different basket cell subtypes. Specific properties of these inhibitory synapses differently control hippocampal functions. Fast-spiking (FS) interneurons exert a tight temporal control of network activities, and support feed-forward inhibition. Conversely, cannabinoid receptor 1(CB1R)-positive basket cells generate feedback inhibition and were proposed to control mood and emotional states. Alterations of GABA release from specific soma-targeting interneurons might thus result in mood disorders. Here we studied the effects on inhibitory neurotransmission onto CA1 hippocampal pyramidal cells of two major antidepressants: imipramine, a tricyclic antidepressant and fluoxetine, a selective serotonin reuptake inhibitor. Application of either drug strongly reduced evoked inhibitory postsynaptic currents and increased the excitation-inhibition ratio on pyramidal neurons in acute slices from rodents. These effects had a presynaptic origin and were independent of the known actions of these drugs on aminergic reuptake systems. Interestingly, antidepressants affected selective inhibitory circuits, as both drugs reduced feed-forward inhibition, leaving the CB1R-sensitive feedback loop unaffected. Pair recordings of unitary synaptic responses between identified basket cells and pyramidal neurons showed that these antidepressants reduced inhibition originating from FS cells, but not from CB1R+ interneurons. Despite their widespread use in clinic, the precise mechanism of action of antidepressant drugs is still debated. Our results demonstrate that hippocampal inhibitory circuits are selectively and directly affected by two major antidepressants and suggest a new mechanism of action of these drugs in the central nervous system. We are currently testing how this selective suppression of feed-forward inhibition affects network hippocampal activities. Conference: EMBO workshop: Gaba Signalling and Brain Networks , Amsterdam, Netherlands, 30 Jun - 2 Jul, 2010. Presentation Type: Poster Presentation Topic: Posters Citation: Bacci A, Mendez P and Pazienti A (2010). Direct Action of two major Antidepressants on a Specific Inhibitory Circuit of the Hippocampus. Conference Abstract: EMBO workshop: Gaba Signalling and Brain Networks . doi: 10.3389/conf.fnins.2010.15.00016 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: 24 Jun 2010; Published Online: 24 Jun 2010. * Correspondence: P. Mendez, European Brain Research Institute, Rome, Italy, p.mendez@ebri.it 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 A. Bacci P. Mendez A. Pazienti Google A. Bacci P. Mendez A. Pazienti Google Scholar A. Bacci P. Mendez A. Pazienti PubMed A. Bacci P. Mendez A. Pazienti 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.

Pericellular innervation of neurons expressing abnormally hyperphosphorylated tau in the hippocampal formation of Alzheimer’s disease patients

Neurofibrillary tangles (NFT) represent one of the main neuropathological features in the cerebral cortex associated with Alzheimer's disease (AD). This neurofibrillary lesion involves the accumulation of abnormally hyperphosphorylated or abnormally phosphorylated microtubule-associated protein tau into paired helical filaments (PHF-tau) within neurons. We have used immunocytochemical techniques and confocal microscopy reconstructions to examine the distribution of PHF-tau-immunoreactive (ir) cells, and their perisomatic GABAergic and glutamatergic innervations in the hippocampal formation and adjacent cortex of AD patients. Furthermore, correlative light and electron microscopy was employed to examine these neurons and the perisomatic synapses. We observed two patterns of staining in PHF-tau-ir neurons, pattern I (without NFT) and pattern II (with NFT), the distribution of which varies according to the cortical layer and area. Furthermore, the distribution of both GABAergic and glutamatergic terminals around the soma and proximal processes of PHF-tau-ir neurons does not seem to be altered as it is indistinguishable from both control cases and from adjacent neurons that did not contain PHF-tau. At the electron microscope level, a normal looking neuropil with typical symmetric and asymmetric synapses was observed around PHF-tau-ir neurons. These observations suggest that the synaptic connectivity around the perisomatic region of these PHF-tau-ir neurons was apparently unaltered.

Computational modeling of high-frequency oscillations at the onset of neocortical partial seizures: From ‘altered structure’ to ‘dysfunction’

In this paper, a neural mass model is proposed to analyze some mechanisms underlying the generation of fast oscillations (80 Hz and beyond) at the onset of seizures. This model includes one sub-population of pyramidal cells and one sub-population of interneurons targeting the perisomatic region of pyramidal cells where fast GABAergic currents are mediated. We identified some conditions for which the model can reproduce the features of high-frequency, chirp-like (from ∼100 to ∼70 Hz) signatures observed in real depth-EEG signals recorded in epileptic patients at seizure onset (“fast onset activity”). These conditions included appropriate alterations in (i) the strengths of GABAergic and glutamatergic connections, and (ii) the amplitude of average EPSPs/IPSPs. Results revealed that a subtle balance between excitatory and inhibitory feedbacks is required in the model for reproducing a ‘realistic’ fast activity, i.e., showing a reduction of frequency with a simultaneous increase in amplitude, as actually observed in epileptogenic cerebral cortex. Results also demonstrated that the number of scenarios (variation, in time, of model parameters) leading to chirp-like signatures was rather limited. First, to produce high-frequency output signals, the model should operate in a “resonance” region, at the frontier between a stable and an unstable region. Second both EPSP and IPSP amplitudes should decrease with time in order to obey the frequency/amplitude constraint. These scenarios obtained through a mathematical analysis of the model show how some alteration in the structure of neural networks can lead to dysfunction. They also provide insights into potentially important mechanisms for high-frequency epileptic activity generation.

Perisomatic‐targeting granule cells in the mouse olfactory bulb

Inhibitory interneurons in the hippocampus and neocortex are differentiated into several morphological and functional subtypes that innervate distinct subcellular domains of principal neurons. In the olfactory bulb (OB), odor information is processed by local neuronal circuits that include the major inhibitory interneuron, granule cells (GCs). All GCs reported to date target their inhibitory output synapses mainly to dendrites of mitral cells (MCs) and tufted cells (TCs) in the external plexiform layer (EPL). Here we identified a novel type of GC that targets output synapses selectively to the perisomatic region of MCs. In the OB of adult transgenic mice expressing green fluorescent protein (GFP) under the control of nestin gene regulatory regions, we observed cells in the granule cell layer (GCL) that have GC-like morphology and strongly express GFP (referred to as type S cells). Type S cells expressed NeuN and GAD67, molecular markers for GCs. Intracellular labeling of type S cells revealed that their dendrites did not enter the EPL, but formed branches and spines within the GCL, internal plexiform layer, and mitral cell layer. Type S cells typically had huge spines at the ends of the apical dendrites. Some of the terminal spines attached to the perisomatic region of MCs and formed dendrosomatic reciprocal synapses with a presumed granule-to-mitral inhibitory synapse and a mitral-to-granule excitatory synapse. These findings indicate the morphological differentiation of GCs into dendritic-targeting and perisomatic-targeting subsets, and suggest the functional differentiation of the GC subsets in the processing of odor information in the OB.

Membrane potential response profiles of CA1 pyramidal cells probed with voltage-sensitive dye optical imaging in rat hippocampal slices reveal the impact of GABA A-mediated feed-forward inhibition in signal propagation

The spatial and temporal distribution of excitatory and inhibitory membrane potential responses on a cell plays an important role in neuronal calculations in local neuronal circuits in the brain. The electrical dynamics of excitatory and inhibitory inputs along the somatodendritic extent of CA1 pyramidal cells during circuit activation were examined by stimulating strata radiatum (SR), oriens (SO), and lacunosum-moleculare (SLM) and measuring laminar responses with voltage-sensitive dye (VSD) optical recording methods. We first confirmed the linearity of the optical signal by comparing fluorescence changes in CA1 to global membrane potential changes when slices were bathed in high-potassium ([K +] O = 25 mM) solution. Except for a TTX-sensitive component in stratum pyramidale, fluorescence changes were equal in all strata, indicating that VSD sensitivity had reasonable linearity across layers. We then compared membrane potential profiles in slices exposed to picrotoxin, a GABA A receptor antagonist. We attributed the picrotoxin-induced changes in the first peak of the excitatory membrane potential to feed-forward inhibition and the later response (appearing 30 ms after stimulation) to feedback inhibition. A difference in feed-forward components was observed in perisomatic and distal apical dendritic regions after SR stimulation. SLM stimulation produced large differences in perisomatic and apical dendritic regions. SO stimulation, however, produced no feed-forward inhibition at the perisomatic region, but produces feed-forward inhibition in distal dendritic regions. These results suggest that actual inhibition of membrane potential response by feed-forward inhibition is greater at perisomatic regions after SR or SLM stimulation but is smaller at distal dendritic regions after SR, SO, and SLM stimulation.

Diminished perisomatic GABAergic terminals on cortical neurons adjacent to amyloid plaques

One of the main pathological hallmarks of Alzheimer's disease (AD) is the accumulation of plaques in the cerebral cortex, which may appear either in the neuropil or in direct association with neuronal somata. Since different axonal systems innervate the dendritic (mostly glutamatergic) and perisomatic (mostly GABAergic) regions of neurons, the accumulation of plaques in the neuropil or associated with the soma might produce different alterations to synaptic circuits. We have used a variety of conventional light, confocal and electron microscopy techniques to study their relationship with neuronal somata in the cerebral cortex from AD patients and APP/PS1 transgenic mice. The main finding was that the membrane surfaces of neurons (mainly pyramidal cells) in contact with plaques lack GABAergic perisomatic synapses. Since these perisomatic synapses are thought to exert a strong influence on the output of pyramidal cells, their loss may lead to the hyperactivity of the neurons in contact with plaques. These results suggest that plaques modify circuits in a more selective manner than previously thought.

Predicting synchrony and asynchrony in basket cell networks coupled by multiple dendritic gap junctions

Basket cells in hippocampus form mutually inhibitory networks and target perisomatic regions of the output pyramidal cell population. Furthermore, they are major players in producing gamma rhythms both in vitro and in vivo [e.g., [2,3]]. Network models incorporating experimentally derived synaptic characteristics produce robust and coherent gamma oscillations, thus suggesting that synchronous output from basket cell networks are important contributors to gamma rhythms. In addition to inhibitory synapses, PV+ basket cells are electrically coupled with gap junctions at multiple locations between their apical and basal dendrites, several hundred microns from their somata [4]. Given that direct electrical communication between neurons plays an important role in shaping network output, it is important to understand how non-proximally located gap junctions contribute to produce synchronous output in basket cell networks. In a previous study we built compartmental models of basket cells with active dendrites and showed that when gap junctions are located distally, there could be sensitive tuning of network dynamics with changes in gap junction conductances [5]. In the work here we built compartmental models of basket cells with different distributions of ion channels in basal and apical dendrites, and explored the dynamics of two-cell networks coupled at non-proximal locations. We first compared full (372 compartments) and reduced (3 compartments) compartmental models to define synchronous and asynchronous regimes. We then quantified phase response curve characteristics in terms of their skewness to predict the network dynamics (synchronous or asynchronous) of reduced models using weakly coupled oscillatory theory. We found that the predictions from quantified phase response curves also held reasonably well when the full compartmental models were coupled at basal or apical dendrites. We next built two-cell networks that were coupled at two and three locations, and computed the average of each of the phase response curves obtained for the different coupling sites. We found that the quantification applied to the averaged phase response curves correctly predicted the network output. This suggests that quantification of phase response curves can be used to predict the output of networks that are coupled with gap junctions at more than one location.

Serotonin differentially modulates the intrinsic properties of spinal motoneurons from the adult turtle

This report considers serotonergic (5-HT) effects on spinal motoneurons, reviewing previous data and presenting a new study showing distinct effects of two 5-HT receptor subtypes. We previously investigated the effects of 5-HT on motoneurons in a slice preparation from the spinal cord of the adult turtle. In agreement with previous studies, we had found that 5-HT applied to the extracellular medium promoted a voltage sensitive plateau potential. However, we also reported that this effect was only observed in half of the motoneurons; 5-HT inhibited the firing of the other half of the motoneurons recorded from. To investigate the reasons for this, we applied 5-HT focally by means of the microiontophoresis technique. Facilitation of plateau potentials was observed when 5-HT was released at sites throughout the somatodendritic region. However, motoneurons were inhibited by 5-HT when selectively applied in the perisomatic region. These two effects could be induced in the same motoneuron. With pharmacological tools, we demonstrate here that the facilitation of plateau potentials is mediated by 5-HT(2) receptors and the inhibitory effect is due to the activation of 5-HT(1A/7) receptors.

Loss of GABAergic neurons in the subiculum and its functional implications in temporal lobe epilepsy

Clinical and experimental evidence suggest that the subiculum plays an important role in the maintenance of temporal lobe seizures. Using the pilocarpine-model of temporal lobe epilepsy (TLE), the present study examines the vulnerability of GABAergic subicular interneurons to recurrent seizures and determines its functional implications. In the subiculum of pilocarpine-treated animals, the density of glutamic acid decarboxylase (GAD) mRNA-positive cells was reduced in all layers. Our data indicate a substantial loss of parvalbumin-immunoreactive neurons in the pyramidal cell and molecular layer whereas calretinin-immunoreactive cells were predominantly reduced in the molecular layer. Though the subiculum of pilocarpine-treated rats showed an increased intensity of GAD65 immunoreactivity, the density of GAD65 containing synaptic terminals in the pyramidal cell layer was decreased indicating an increase in the GAD65 intensity of surviving synaptic terminals. We observed a decrease in evoked inhibitory post-synaptic currents that mediate dendritic inhibition as well as a decline in the frequency of miniature inhibitory post-synaptic currents (mIPSCs) that are restricted to the perisomatic region. The decrease in mIPSC frequency (-30%) matched with the reduced number of perisomatic GAD-positive terminals (-28%) suggesting a decrease of pre-synaptic GABAergic input onto pyramidal cells in epileptic animals. Though cell loss in the subiculum has not been considered as a pathogenic factor in human and experimental TLE, our data suggest that the vulnerability of subicular GABAergic interneurons causes an input-specific disturbance of the subicular inhibitory system.

Tracing ‘driver’ versus ‘modulator’ information flow throughout large-scale, task-related neural circuitry

PRIMARY OBJECTIVE: To determine the relative uses of neural action potential ('spike') data versus local field potentials (LFPs) for modeling information flow through complex brain networks. HYPOTHESIS: The common use of LFP data, which are continuous and therefore more mathematically suited for spectral information-flow modeling techniques such as Granger causality analysis, can lead to spurious inferences about whether a given brain area 'drives' the spiking in a downstream area. EXPERIMENT: We recorded spikes and LFPs from the forelimb motor cortex (M1) and the magnocellular red nucleus (mRN), which receives axon collaterals from M1 projection cells onto its distal dendrites, but not onto its perisomatic regions, as rats performed a skilled reaching task. RESULTS AND IMPLICATIONS: As predicted, Granger causality analysis on the LFPs-which are mainly composed of vector-summed dendritic currents-produced results that if conventionally interpreted would suggest that the M1 cells drove spike firing in the mRN, whereas analyses of spiking in the two recorded regions revealed no significant correlations. These results suggest that mathematical models of information flow should treat the sampled dendritic activity as more likely to reflect intrinsic dendritic and input-related processing in neural networks, whereas spikes are more likely to provide information about the output of neural network processing.