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Smooth functional and structural maps on the neocortex via orthonormal bases of the Laplace-Beltrami operator.

Functional and structural maps, such as a curvature, cortical thickness, and functional magnetic resonance imaging (MRI) maps, indexed over the local coordinates of the cortical manifold play an important role in neuropsychiatric studies. Due to the highly convoluted nature of the cerebral cortex and image quality, these functions are generally uninterpretable without proper methods of association and smoothness onto the local coordinate system. In this paper, we generalized the spline smoothing problem (Wahba, 1990) from a sphere to any arbitrary two-dimensional (2-D) manifold with boundaries. We first seek a numerical solution to orthonormal basis functions of the Laplace-Beltrami (LB) operator with Neumann boundary conditions for a 2-D manifold M then solve the spline smoothing problem in a reproducing kernel Hilbert space (r.k.h.s.) of real-valued functions on manifold M with kernel constructed from the basis functions. The explicit discrete LB representation is derived using the finite element method calculated directly on the manifold coordinates so that finding discrete LB orthonormal basis functions is equivalent to solving an algebraic eigenvalue problem. And then smoothed functions in r.k.h.s can be represented as a linear combination of the basis functions. We demonstrate numerical solutions of spherical harmonics on a unit sphere and brain orthonormal basis functions on a planum temporale manifold. Then synthetic data is used to quantify the goodness of the smoothness compared with the ground truth and discuss how many basis functions should be incorporated in the smoothing. We present applications of our approach to smoothing sulcal mean curvature, cortical thickness, and functional statistical maps on submanifolds of the neocortex.

Algorithms↗

Optical imaging of epileptiform activity in human neocortex.

The surgical outcomes of patients suffering from neocortical epilepsy are not as successful as the surgical outcomes from resections of epilepsy patients with mesial temporal sclerosis. The main difficulty in the treatment of neocortical epilepsy is that current technology has limited accuracy in mapping neocortical epileptogenic tissue. It is known that the optical spectroscopic properties of brain tissue are correlated with changes in neuronal activity. The method of mapping these activity-evoked optical changes is known as imaging of intrinsic optical signals (IIOS). Activity-evoked optical changes measured in neocortex are generated by changes in cerebral hemodynamics (i.e., changes in blood oxygenation and blood volume). Our experimental approach was to acquire high-resolution IIOS maps of epileptiform activity in patients undergoing surgery for medically intractable neocortical epilepsy. Both spontaneous and stimulation-evoked epileptiform activity was monitored. Imaging of intrinsic optical signals was able to localize neocortical epileptic foci precisely by using changes in blood volume in contrast to changes in blood oxygenation. IIOS has the potential to translate from a purely research tool to a new intraoperative approach for the surgical treatment of neocortical epilepsy.

Blood Volume↗

Organization of GABA receptor alpha-subunit clustering in the developing rat neocortex and hippocampus.

We compared the expression and co-expression of alpha1, alpha2, alpha3, and alpha5-subunit protein clusters of the gamma-aminobutyric acid (GABA)(A) receptor in the neocortex and hippocampus of rat at postnatal days (PND) 5-10 and 30-40 in order to understand how inhibitory receptors reorganize during brain maturation. The size, intensity, density and pattern of co-localization of fluorescently tagged subunit clusters were determined in deconvolved digital images using a novel 2D cross-correlational analysis. The cross-correlation analysis allowed an unbiased identification of GABA(A) receptor subunit clusters based on staining intensity. Cluster size increased through development; only the alpha2 clusters in dentate gyrus (DG) decreased in size. alpha5-subunit cluster density either increased or decreased with maturation depending on the brain region. For the other subunits, the cluster density remained rather constant, with noted exceptions (increase in alpha2 clusters in cortical layer 5 but a decrease of alpha3 clusters in hilus). The co-localization of alpha1-subunit with the others was unique and not correlated to overall changes in subunit abundance between developmental époques. So, although alpha2-subunit expression went up in the DG, the clusters became less co-localized with alpha1. In contrast, alpha5-subunit clusters became more co-localized with alpha1 as the alpha5-subunit expression declined in cortex and CA1. The co-localization of alpha3 with alpha1 also became greater in layer 6. In the adult brain not all clustering was associated with synapses, as many alpha-subunit clusters did not co-localize with synaptophysin. Overall, these data indicate that the regulation of GABA(A) receptor clustering is both synaptic and extrasynaptic, presumably reflecting complex cellular trafficking mechanisms.

Aging↗

A transmission electron microscopic study of microglia/macrophages in the hippocampal cortex and neocortex following chronic exposure to valproate.

In chronic administration of sodium valproate to rats, significant disorders of structural integrity of the hippocampal gyrus and the neocortex of the temporal lobe, observed in the last two stages of the experiment (after 9 and 12 months), coexisted with increased number of microglial cells and, especially after 12 months, with intense phagocytic activity within these cells. At the ultrastructural level, phagocyte microglial cells were hypertrophied with several broadened processes. Their cytoplasm contained rich lysosomal apparatus, numerous lipofuscin-like structures, lipid droplets and multilaminated bodies. The nuclei of these cells were characteristic oval or round and sometimes triangle in shape with dense and highly clumped heterochromatin, distinctly accumulated under nuclear envelope, and sparse euchromatin. Microglia/macrophages were frequently present in a close vicinity of changed neuronal somata and also close to the altered elements of the neuropil pyramidal layer of the cortex. Microglial response may, together with abnormalities in neurones, astroglia and blood-brain barrier, play a significant role in the development of experimental valproate encephalopathy.

Animals↗

Homer 1a enhances spike-induced calcium influx via L-type calcium channels in neocortex pyramidal cells.

The scaffold protein family Homer/Vesl serves to couple surface receptors or channels with endoplasmic calcium release channels. Homer 1a/Vesl-1S is regarded as regulating such coupling in an activity-dependent manner. The present calcium photometry and electrophysiological measurement revealed that Homer 1a up-regulates voltage-dependent calcium channels (VDCCs), depending on inositol-1,4,5-trisphosphate (IP3) receptors (IP3Rs). In rat neocortex pyramidal cells, intracellular injection by diffusion from the patch pipette (referred to as 'infusion') of Homer 1a protein enhanced spike-induced calcium increase, depending on both the protein concentration and spike frequency. Induction of this enhancement was disrupted by blockers of key molecules of the mGluR-IP3 signalling pathway, including metabotropic glutamate receptors (mGluRs), phospholipase C and IP3Rs. However, infusion of IP3 failed to mimic the effect of Homer 1a, suggesting requirement for a second Homer 1a-mediated signalling as well as the mGluR-IP3 signalling. In contrast to the induction, maintenance of this enhancement was independent of the mGluR-IP3 signalling, taking the form of augmented calcium influx via L-type VDCCs. Presumably due to the VDCC up-regulation, threshold currents for calcium spikes were reduced. Given that Homer 1a induction is thought to down-regulate neural excitability and hence somatic spike firing, this facilitation of calcium spikes concomitant with such attenuated firing may well have a critical impact on bi-directional synaptic plasticity.

Animals↗

Estradiol stimulates progenitor cell division in the ventricular and subventricular zones of the embryonic neocortex.

Two distinct populations of cerebral cortical progenitor cells that generate neurons during embryogenesis have been identified: radial glial cells and intermediate progenitor cells. Despite advances in our understanding of progenitor cell populations, we know relatively little about factors that regulate their proliferative behaviour. 17-beta-Estradiol (E2) is present in the adult and developing mammalian brain, and plays an important role in central nervous system processes such as neuronal differentiation, survival and plasticity. E2 also stimulates neurogenesis in the adult dentate gyrus. We examined the role of E2 during embryonic cortical neurogenesis through immunohistochemistry, in situ hybridization, functional enzyme assay, organotypic culture and in utero administration of estradiol-blocking agents in mice. We show that aromatase, the E2 synthesizing enzyme, is present in the embryonic neocortex, that estrogen receptor-alpha is present in progenitor cells during cortical neurogenesis, that in vitro E2 administration rapidly promotes proliferation, and that in utero blockade of estrogen receptors decreases proliferation of embryonic cortical progenitor cells. Furthermore, the E2 inhibitor alpha-fetoprotein is expressed at high levels by radial glial cells but at lower levels by intermediate progenitor cells, suggesting that E2 differentially influences the proliferation of these cortical progenitor cell types. These findings demonstrate a new functional role for E2 as a proliferative agent during critical stages of cerebral cortex development.

Androstenedione↗

Premature bifurcation of the apical dendritic trunk of vibrissa-responding pyramidal neurones of X-irradiated rat neocortex.

1. Electrophysiological and morphological experiments were performed on the pyramidal neurones of the somatosensory neocortex of the adult rat that had been exposed in utero to 200 rad of X-irradiation. Under urethane anaesthesia, evoked gross potentials, extracellular and intracellular neuronal responses, and laminar field potentials were recorded. The evoked epicortical potential to deflection of a single whisker was a long-lasting positive wave which contrasted with a biphasic positive-negative complex in unirradiated controls. Neurones were initially tested during extracellular recording for responses to whisker deflections. This was followed by intracellular injection with horseradish peroxidase (HRP), and the HRP-stained neuronal elements were visualized using diaminobenzidine as a chromagen. 2. Fifty neurones were recorded and stained through the soma. The mean response latency was 15.1 ms. Of these, thirty-six showed premature bifurcation of the apical dendrite. The angle of bifurcation of the apical dendrite was measured in the coronal plane and was found to be a function of the depth at which the soma was located and the distance between the soma and bifurcation point. It was suggested that the apical dendrites of these neurones underwent premature bifurcation due to an imbalance between the growth of neurones and skull. 3. Fifteen neurones were recorded and stained through the presumed apical dendritic shaft. The mean response latency was 19.5 ms. The electrode track left in the histological specimen pointed to the stained apical dendrite. Dendritic elements distal to the entry point were preferentially filled with HRP. In no cases were somata stained. There was, in turn, no evidence of recording from dendritic elements distal to the bifurcation since no electrode track was found to point to these elements. That dendritic spike responses may not travel beyond the bifurcation was further substantiated by laminar analysis of field potentials.

Algorithms↗

Dendritic release of glutamate suppresses synaptic inhibition of pyramidal neurons in rat neocortex.

Dual whole-cell recordings were made in layer 2/3 of the rat neocortex in synaptically connected pyramidal cells and fast-spiking non-accommodating (FSN) interneurons. In 75% of cell pairs (n = 80), the cells formed reciprocal synaptic connections. Trains of backpropagating action potentials in pyramidal cells induced Ca2+ transients in dendrites followed by inhibition of unitary IPSPs. IPSP depression was prevented by loading pyramidal cells with 5 mM BAPTA or EGTA. IPSP depression was mimicked by the metabotropic glutamate receptor (mGluR) agonist ACPD and was prevented by a mixture of the mGluR antagonists CPCCOEt and EGLU.IPSP depression was prevented by loading pyramidal cells with the antagonists of vesicular exocytosis botulinum toxin D (light chain) and GDP-beta-S. It is concluded that Ca2+-dependent release of a retrograde messenger, most probably glutamate, from pyramidal cell dendrites suppresses the inhibition of pyramidal neurons via activation of mGluRs located in FSN interneuron nerve terminals.

Action Potentials↗

Calcium dynamics associated with action potentials in single nerve terminals of pyramidal cells in layer 2/3 of the young rat neocortex.

Calcium dynamics associated with a single action potential (AP) were studied in single boutons of the axonal arbor of layer 2/3 pyramidal cells in the neocortex of young (P14-16) rats. We used fluorescence imaging with two-photon excitation and Ca2+-selective fluorescence indicators to measure volume-averaged Ca2+ signals. These rapidly reached a peak (in about 1 ms) and then decayed more slowly (tens to hundreds of milliseconds). Single APs and trains of APs reliably evoked Ca2+ transients in en passant boutons located on axon collaterals in cortical layers 2/3, 4 and 5, indicating that APs propagate actively and reliably throughout the axonal arbor. Branch point failures are unlikely to contribute to differences in synaptic efficacy and reliability in the connections made by layer 2/3 pyramidal cells. AP-evoked Ca2+ transients in boutons were mediated by voltage-dependent Ca2+ channels (VDCCs), predominantly by the P/Q- and N-subtypes. Ca2+ transients were, on average, of significantly larger amplitude in boutons than in the flanking segments of the axon collateral. Large amplitude Ca2+ transients in boutons were spatially restricted to within <= 3 m of axonal length. Single AP-evoked Ca2+ transients varied up to 10-fold across different boutons even if they were located on the same axon collateral. In contrast, variation of Ca2+ transients evoked by successive APs in a given single bouton was small (coefficient of variation, c.v. <= 0.21). Amplitudes of AP-evoked Ca2+ signals did not correlate with the distance of boutons from the soma. In contrast, AP-evoked Ca2+ signals in spines of basal dendrites decreased slightly (correlation coefficient, r2 = -0.27) with distance from the soma. Measurements with the low-affinity Ca2+ indicator Magnesium Green suggest that the volume-averaged residual free [Ca2+]i in a bouton increases on average by 500 nM following a single AP. Higher concentrations of indicator caused, on average, a decrease in the amplitude and an increase in the decay time constant of Ca2+ transients. Assuming a single-compartment model the concentration dependence of decay time constants suggests a low endogenous Ca2+ binding ratio close to 140, indicating that of the total Ca2+ influx ( approximately 2 fC) less than 1% remained free. The indicator concentration dependence of decay time constants further suggests that the residual free Delta[Ca2+]i associated with an AP decays with a time constant of about 60 ms (35 C) reflecting a high Ca2+ extrusion rate of about 2600 s(-1). The results show that AP-evoked volume-averaged Ca2+ transients in single boutons are evoked reliably and, on average, have larger amplitudes than Ca2+ transients in other subcellular compartments of layer 2/3 pyramidal cells. A major functional signature is the large variation in the amplitude of Ca2+ transients between different boutons. This could indicate that local interactions between boutons and different target cells modify the spatiotemporal Ca2+ dynamics in boutons and cause target cell-specific differences in their transmitter release properties.

Action Potentials↗

Inhibition of D-serine accumulation in the Xenopus oocyte by expression of the rat ortholog of human 3'-phosphoadenosine 5'-phosphosulfate transporter gene isolated from the neocortex as D-serine modulator-1.

D-serine in mammalian brains has been suggested to be an endogenous co-agonist of the NMDA-type glutamate receptor. We have explored the molecules regulating D-serine uptake and release from the rat neocortex cDNA library using a Xenopus oocyte expression system, and isolated a cDNA clone designated as dsm-1 (D-serine modulator-1) encoding a protein that reduces the accumulation of D-serine to the oocyte. dsm-1 is the rat orthologue of the human 3'-phosphoadenosine 5'-phosphosulfate transporter 1 (PAPST1) gene. The hydropathy analysis of the deduced amino acid sequence of the Dsm-1 protein predicts the 10 transmembrane domains with a long hydrophobic stretch in the C-terminal like some amino acid transporters. The dsm-1 mRNA is predominantly expressed in the forebrain areas that are enriched with D-serine and NMDA receptors, and in the liver. The transient expression of dsm-1 in COS-7 cells demonstrates a partially Golgi apparatus-related punctuate distribution throughout the cytoplasm with a concentration near the nucleus. dsm-1-expressing oocytes diminishes the sodium-dependent and -independent accumulation of D-serine and the basal levels of the intrinsic D-serine and increases the rate of release of the pre-loaded D-serine. These findings indicate that dsm-1 may, at least in part, be involved in the D-serine translocation across the vesicular or plasma membranes in the brain, and thereby control the extra- and intracellular contents of D-serine.

Amino Acid Sequence↗

Cloning of a D-serine-regulated transcript dsr-2 from rat cerebral neocortex.

D-serine is now considered to be an endogenous co-agonist of the NMDA receptor in mammalian brain. To obtain insight into the molecular mechanisms underlying D-serine metabolism and function, we explored transcripts that are responsive to D-serine in the neocortex of the 8-day-old infant rat by a differential cloning technique, RNA arbitrarily primed PCR. We isolated a novel D-serine inducible transcript, D-serine-responsive transcript-2 (dsr-2), that was exclusively expressed in the brain. Sequence analysis of the corresponding cDNAs to the transcript revealed that the dsr-2 mRNA consists of 7199 nucleotides with an open reading frame encoding 111 amino acids. The dsr-2 gene was located on the reverse strand within an intron of the neurexin-3alpha gene, mapped to rat chromosome 6q24-31. The regional distribution of the basal expression of dsr-2 and its ontogenic changes in the brain closely correlated with those of free D-serine and of NMDA receptor R2B subunit mRNA, but were somewhat different from those of the neurexin-3alpha transcript. These findings suggest that dsr-2 may be involved in D-serine metabolism and/or function, and in the interactions between D-serine, NMDA receptor and neurexin-3alpha, in mammalian brain.

Adenosine Triphosphatases↗

Layer-specific pathways for the horizontal propagation of epileptiform discharges in neocortex.

PURPOSE: Epileptiform discharges that resemble interictal spikes can be generated by slices of neocortex treated with antagonists of gamma-aminobutyric acid A (GABA(A)) receptors. These discharges can propagate horizontally for long distances. We tested the hypothesis that propagation occurs through preferred horizontal pathways that lie in a particular cortical layer. METHODS: Slices were prepared from the primary somatosensory cortex of rats, maintained in vitro, and bathed with the GABA(A) receptor antagonist picrotoxin. Electrical stimuli were used to evoke single all-or-none paroxysmal field potentials (PFP) that were recorded with pairs or arrays of field potential electrodes. RESULTS: To test which laminae are necessary for propagation, vertical cuts were made to force the PFP to spread horizontally through particular layers. If slices were bathed in a high dose of picrotoxin (35 microM), a bridge of cortex 350 microm thick placed at any lamina was sufficient to support PFP propagation. However, in low picrotoxin doses (2.5 microM), similarly sized bridges had to include tissue from layers 4/5 or 5/6 to support propagation. When slices were cut horizontally (i.e., parallel to the pia) in strips. either upper-, middle-, or lower-layer strips were sufficient to support PFP propagation if the picrotoxin concentration was high; however, in low picrotoxin doses, only horizontal strips that included layer 5 could support propagation. Finally, in intact picrotoxin-treated slices, focal applications of GABA were systematically applied to different laminae as the PFP propagated past; GABA was most effective at blocking or delaying propagation when it was applied to layer 5b. CONCLUSIONS: We conclude that epileptiform propagation can occur through a variety of horizontal pathways when cortical inhibition is strongly impaired. However, when inhibition is reduced only moderately, axonal pathways in layer 5 are critical for seizure spread.

Animals↗

Brain hypometabolism in a model of chronic focal epilepsy in rat neocortex.

PURPOSE: Metabolic mapping of the human brain has become a widely used method for identifying and localizing epileptic foci. A reduction of glucose consumption usually is found interictally in the area of the focus. By contrast, animal models of acute epilepsy show a hypermetabolism in the epileptic focus. Here we investigated how metabolism is altered in an animal model of chronic epilepsy caused by focal injection of tetanus toxin into rat neocortex. METHODS: A total of 27 male Wistar rats were anesthetized and injected into the motor or sensory cortex either with dissolved tetanus toxin or with the solvent only. Animals recovered for 7, 14, or 30 days and then were anesthetized again for quantitative 14C-deoxyglucose autoradiography. Data were analyzed with an imaging program, and regional cerebral glucose metabolism (rCMRGlc) was determined. RESULTS: Injection of tetanus toxin into the motor cortex caused a focal hypometabolism which was confined to the cytoarchitectonic boundaries of the injected area, whereas sensory cortex injection caused a more widespread hypometabolism in all sensory cortical and connected, areas. None of the animals displayed focal hypermetabolism and we observed no significant time-dependent alteration of brain metabolism. CONCLUSIONS: Tetanus toxin injection into the cortex of the rat induces chronic epileptic activity accompanied by a focal hypometabolism. The data suggest that the spread of the metabolic alterations depends on the connectivity of the injected cortical area.

Animals↗

Epileptiform propagation patterns mediated by NMDA and non-NMDA receptors in rat neocortex.

PURPOSE: The neocortex can generate various forms of epileptiform activity, including one that depends on N-methyl-D-aspartate (NMDA)-type glutamate receptors (NMDARs), and another dependent on non-NMDA-type (AMPA) glutamate receptors (AMPARs). Previous work in vitro suggests that both forms of activity are initiated by neurons of layer 5, but the spatial patterns of horizontal propagation have been studied only for the AMPAR form. We have tested the hypothesis that both types of epileptiform activity spread via common pathways in one cortical layer, suggesting that lamina-specific intervention might selectively interrupt both. METHODS: Slices of rat somatosensory cortex were maintained in vitro and treated with the gamma-aminobutyric acid type A (GABA(A))-receptor antagonist picrotoxin. Single all-or-none epileptiform discharges were evoked with an electrical stimulus, and extracellular microelectrodes were used to track the vertical and lateral spread of the discharges. RESULTS: In both high and low concentrations of picrotoxin, the non-NMDAR antagonist 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) completely blocked propagation, whereas the NMDAR antagonist D-2-amino-5-phosphonovaleric acid (DAPV) only shortened the duration of discharges. When extracellular [Mg2+] was reduced in the presence of picrotoxin and CNQX, NMDAR-dependent epileptiform discharges could be initiated. NMDAR-dependent discharges spread at about one fifth the conduction velocity of AMPAR-dependent events. Analysis of spatiotemporal field-potential patterns suggested that both NMDAR- and AMPAR-mediated propagation involved early activity in layers 5 and 6, followed by larger-amplitude activity in upper cortical layers along the path of propagation. CONCLUSIONS: Our results imply that a common pathway mediates the propagation of these two forms of epileptiform activity, and suggests that lamina-specific surgical intervention might maximize anticonvulsant effect while minimally disrupting cortical function.

2-Amino-5-phosphonovalerate↗

Quinine, a blocker of neuronal cx36 channels, suppresses seizure activity in rat neocortex in vivo.

PURPOSE: The selective contribution of neuronal gap junction (GJ) communication via connexin 36 (Cx36) channels to epileptogenesis and to the maintenance and propagation of seizures was investigated in both the primary focus and the mirror focus by using pharmacologic approaches with the 4-aminopyridine in vivo epilepsy model. METHODS: ECoG recording was performed on anesthetized adult rats, in which either quinine, a selective blocker of Cx36, or the broad-spectrum GJ blockers carbenoxolone and octanol were applied locally, before the induction or at already active epileptic foci. RESULTS: The blockade of Cx36 channels by quinine before the induction of epileptiform activity slightly reduced the epileptogenesis. When quinine was applied after 25-30 repetitions of seizures, a new discharge pattern appeared with frequencies >15 Hz at the initiation of seizures. In spite of the increased number of seizures, the summated ictal activity decreased, because of the significant reduction in the duration of the seizures. The amplitudes of the seizure discharges of all the patterns decreased, with the exception of those with frequencies of 11-12 Hz. The blockade of Cx36 channels and the global blockade of the GJ channels resulted in qualitatively different modifications in ictogenesis. CONCLUSIONS: The blockade of Cx36 channels at the already active epileptic focus has an anticonvulsive effect and modifies the manifestation of the 1- to 18-Hz seizure discharges. Our findings indicate that the GJ communication via Cx36 channels is differently involved in the synchronization of the activities of the networks generating seizure discharges with different frequencies. Additionally, we conclude that both neuronal and glial GJ communication contribute to the manifestation and propagation of seizures in the adult rat neocortex.

4-Aminopyridine↗

Enhanced GABA(A) receptor-mediated activity following activation of NMDA receptors in Cajal-Retzius cells in the developing mouse neocortex.

Cajal-Retzius (CR) cells are among the earliest generated population of neurons in the developing neocortex and have been implicated in regulating cortical lamination. In rodents, CR cells are transient, being present only up to 2-3 weeks after birth. Although previous electrophysiological studies have demonstrated the presence of NMDA and GABAA receptors in CR cells, little is known about the functional properties of these receptors. Using whole-cell patch-clamp techniques in neocortical slices, we confirmed the presence of D-aminophosphonovaleric acid (APV)- and ifenprodil-sensitive NMDA receptors, and found that the functional expression of this receptor subtype is strain specific. The NMDA-induced response was consistently accompanied by overriding current transients that were blocked by APV and ifenprodil. In addition, bicuculline readily abolished these transients without affecting the NMDA-induced current response. The generation of these overriding current transients was dependent upon intracellular Ca2+ and was prevented by dialysis with the high-affinity Ca2+-chelator BAPTA. Overall, this study uncovered a synergistic interaction between these receptors, whereby activation of NMDA receptors leads to enhanced GABAA receptor-mediated activity through a Ca2+-dependent mechanism.

Animals↗

Endocannabinoid signalling selectively targets perisomatic inhibitory inputs to pyramidal neurones in juvenile mouse neocortex.

Retrograde synaptic signalling has long been recognized as a fundamental feature of neural systems. However, the cellular specificity and functional consequences of fast retrograde communication are not well understood. We have focused our efforts on understanding the role that endocannabinoids play in regulating synaptic inhibition in sensory neocortex. Recent studies have implicated endocannabinoids as the retrograde signalling molecules that underlie depolarization-induced suppression of inhibition, or DSI. This short-term form of presynaptic depression is triggered by postsynaptic depolarization and is likely to play an important role in information processing. In the present study we investigated the cellular and synaptic specificity of endocannabinoid signalling in sensory cortex using whole-cell recordings from layer 2/3 pyramidal neurones (PNs) in acute brain slices. We report that GABAergic interneurones that are depolarized by muscarinic receptor stimulation provided the majority of DSI-susceptible inputs to neocortical PNs. This subclass of interneurones generated large, fast postsynaptic currents in PNs which were transiently suppressed by either postsynaptic depolarization or a brief train of action potentials. Neocortical DSI required activation of the type 1 cannabinoid receptor (CB1R) but not metabotropic glutamate or GABA receptors. Using focal drug application, we found that the DSI-susceptible afferents preferentially synapse on the perisomatic membrane of PNs, and not on the apical dendrites. Together, these results suggest that endocannabinoid-mediated DSI in the cortex can transiently and selectively depress a subclass of PN inputs. Although the physiological implications remain to be explored, this suppression of somatic inhibition may alter the excitability of principal neurones and thereby modulate cortical output.

Action Potentials↗

SOUND-EVOKED POTENTIALS IN NEOCORTEX OF UNANESTHETIZED OPOSSUM.

Short-latency potentials are evoked by auditory stimuli at all loci of neocortex recorded from, including points in orbital-frontal, visual, and somatosensory areas. These potentials are similar in latency and wave form to responses obtained from the primary auditory projection area in higher mammals, but occur in widely varying spatial patterns.

Animals↗