Probabilistic graphical model identifies clusters of EEG patterns in recordings from neonates.

OBJECTIVES: In this paper we introduce a novel method for the evaluation of neonatal brain function via multivariate EEG (electroencephalography) signal processing and embedding into a probabilistic graph, the so called Chow-Liu tree. METHODS: Using 28 EEG recordings of preterm and term neonate infants the complex features of the EEG signals were constructed in the form of a Chow-Liu tree. The trees were embedded into a 3 dimensional Euclidean space. Clustering of specific EEG patterns was done by complete linkage algorithm. RESULTS: Our analytic tool was able to build clusters of patients with pathological EEG findings. In particular, we were able to make a visual proof on a 3d multidimensional scaling coordinate system with a good performance. The distances (graph edit distance) between Chow-Liu trees of different infants were proportional to the clinical findings of corresponding infants. CONCLUSION: Our method may provide a basis for the future development of a diagnostic/prognostic non-invasive brain monitoring tool which will be able to differentiate between a variety of complex clinical findings. SIGNIFICANCE: This model addresses relevant issues in neonatology and neuropediatrics in terms of identification of possible clinical factors which interfere with normal brain development and will allow fast unbiased recognition of infants with specific pathological EEG findings.

A critical role for VEGF and VEGFR2 in NMDA receptor synaptic function and fear-related behavior.

Vascular endothelial growth factor (VEGF) is known to be required for the action of antidepressant therapies but its impact on brain synaptic function is poorly characterized. Using a combination of electrophysiological, single-molecule imaging and conditional transgenic approaches, we identified the molecular basis of the VEGF effect on synaptic transmission and plasticity. VEGF increases the postsynaptic responses mediated by the N-methyl-D-aspartate type of glutamate receptors (GluNRs) in hippocampal neurons. This is concurrent with the formation of new synapses and with the synaptic recruitment of GluNR expressing the GluN2B subunit (GluNR-2B). VEGF induces a rapid redistribution of GluNR-2B at synaptic sites by increasing the surface dynamics of these receptors within the membrane. Consistently, silencing the expression of the VEGF receptor 2 (VEGFR2) in neural cells impairs hippocampal-dependent synaptic plasticity and consolidation of emotional memory. These findings demonstrated the direct implication of VEGF signaling in neurons via VEGFR2 in proper synaptic function. They highlight the potential of VEGF as a key regulator of GluNR synaptic function and suggest a role for VEGF in new therapeutic approaches targeting GluNR in depression.

GABA transporters control GABAergic neurotransmission in the mouse subplate.

The subplate is a transient layer between the cortical plate and intermediate zone in the developing cortex. Thalamo-cortical axons form temporary synapses on subplate neurons (SPns) before invading the cortical plate. Neuronal activity within the subplate is of critical importance for the development of neocortical circuits and architecture. Although both glutamatergic and GABAergic inputs on SPns were reported, short-term plasticity of GABAergic transmission has not been investigated yet. GABAergic postsynaptic currents (GPSCs) were recorded from SPns in coronal neocortical slices prepared from postnatal day 3-4 mice using whole-cell patch-clamp technique. Evoked GPSCs (eGPSCs) elicited by electrical paired-pulse stimulation demonstrated paired-pulse depression at all interstimulus intervals tested. Baclofen, a specific GABAB receptor (GABABR) agonist, reduced eGPSC amplitudes and increased paired-pulse ratio (PPR), suggesting presynaptic location of functional GABABRs. Baclofen-induced effects were alleviated by (2S)-3-[[(1S)-1-(3,4-dichlorophenyl)ethyl]amino-2-hydroxypropyl](phenylmethyl)phosphinic acid (CGP55845), a selective GABABR blocker. Moreover, CGP55845 increased eGPSC amplitudes and decreased PPR even under control conditions, indicating that GABABRs are tonically activated by ambient GABA. Because extracellular GABA concentration is mainly regulated by GABA transporters (GATs), we asked whether GATs release GABA. 1,2,5,6-tetrahydro-1-[2-[[(diphenylmethylene)amino]oxy]ethyl]-3-pyridinecarboxylic acid (NNC-711) (10µM), a selective GAT-1 blocker, increased eGPSC decay time, decreased eGPSC amplitudes and PPR. The two last effects but not the first one were blocked by CGP55845, indicating that GAT-1 blockade causes an elevation of extracellular GABA concentration and in turn activation of extrasynaptic GABAARs and presynaptic GABABRs. 1-[2-[tris(4-methoxyphenyl)methoxy]ethyl]-(S)-3-piperidinecarboxylic acid (SNAP-5114), a specific GAT-2/3 blocker, failed to affect eGPSC kinetics. However, in contrast to NNC-711 SNAP-5114 increased eGPSC amplitudes and decreased PPR. In the presence of SNAP-5114 CGP55845 did not influence GABAergic transmission, indicating that GABABRs are not activated any longer. We conclude that in the subplate GAT-2/3 operates in reverse mode. GABA released via GAT-2/3 activates presynaptic GABABRs on GABAergic synapses and tonically inhibits GABAergic inputs on SPns.

Methylxanthine-evoked perturbation of spontaneous and evoked activities in isolated newborn rat hippocampal networks.

Treatment of apnea of prematurity with methylxanthines like caffeine, aminophylline or theophylline can evoke hippocampal seizures. However, it is unknown at which interstitial brain concentrations methylxanthines promote such neonatal seizures or interfere with physiological 'early network oscillations' (ENOs) that are considered as pivotal for maturation of hippocampal neural networks. We studied theophylline and caffeine effects on ENOs in CA3 neurons (CA3-ENOs) and CA3 electrical stimulation-evoked monosynaptic CA1 field potentials (CA1-FPs) in sliced and intact hippocampi, respectively, from 8 to 10-days-old rats. Submillimolar doses of theophylline and caffeine, blocking adenosine receptors and phosphodiesterase-4 (PDE4), did not affect CA3-ENOs, ENO-associated cytosolic Ca(2+) transients or CA1-FPs nor did they provoke seizure-like discharges. Low millimolar doses of theophylline (⩾1mM) or caffeine (⩾5mM), blocking GABAA and glycine receptors plus sarcoplasmic-endoplasmic reticulum Ca(2+) ATPase (SERCA)-type Ca(2+) ATPases, evoked seizure-like discharges with no indication of cytosolic Ca(2+) dysregulation. Inhibiting PDE4 with rolipram or glycine receptors with strychnine had no effect on CA3-ENOs and did not occlude seizure-like events as tested with theophylline. GABAA receptor blockade induced seizure-like discharges and occluded theophylline-evoked seizure-like discharges in the slices, but not in the intact hippocampi. In summary, submillimolar methylxanthine concentrations do not acutely affect spontaneous CA3-ENOs or electrically evoked synaptic activities and low millimolar doses are needed to evoke seizure-like discharges in isolated developing hippocampal neural networks. We conclude that mechanisms of methylxanthine-related seizure-like discharges do not involve SERCA inhibition-related neuronal Ca(2+) dysregulation, PDE4 blockade or adenosine and glycine receptor inhibition, whereas GABA(A) receptor blockade may contribute partially.

Cajal-Retzius cells: update on structural and functional properties of these mystic neurons that bridged the 20th century.

Cajal-Retzius cells (CRc) represent a mostly transient neuronal cell type localized in the uppermost layer of the developing neocortex. The observation that CRc are a major source of the extracellular matrix protein reelin, which is essential for the laminar development of the cerebral cortex, attracted the interest in this unique cell type. In this review we will (i) describe the morphological and molecular properties of neocortical CRc, with a special emphasize on the question which markers can be used to identify CRc, (ii) summarize reports that identified the different developmental origins of CRc, (iii) discuss the fate of CRc, including recent evidence for apoptotic cell death and a possible persistence of some CRc, (iv) provide a detailed description of the electrical membrane properties and transmitter receptors of CRc, and (v) address the role of CRc in early neuronal circuits and cortical development. Finally, we speculate whether CRc may provide a link between early network activity and the structural maturation of neocortical circuits.

Effect of depolarizing GABA(A)-mediated membrane responses on excitability of Cajal-Retzius cells in the immature rat neocortex.

In immature neurons activation of ionotropic GABA receptors induces depolarizing membrane responses due to a high intracellular Cl(-) concentration ([Cl(-)](i)). However, it is difficult to draw conclusions about the functional consequences of subthreshold GABAergic depolarizations, since GABAergic membrane shunting and additional effects on voltage-dependent ion channels or action potential threshold must be considered. To systematically investigate factors that determine the GABAergic effect on neuronal excitability we performed whole cell patch-clamp recordings from Cajal-Retzius cells in immature rat neocortex, using [Cl(-)](i) between 10 and 50 mM. The effect of focal GABA application was quantified by measuring various parameters of GABAergic responses including the shift in minimal threshold current (rheobase). The rheobase shift was correlated with other parameters of the GABAergic responses by multiple linear regression analyses with a set of simple mathematical models. Our experiments demonstrate that focal GABA application induces heterogeneous rheobase shifts in Cajal-Retzius cells that could not be predicted reliably from [Cl(-)](i) or the GABAergic membrane depolarization. Implementation of a linear mathematical model, which takes the GABAergic membrane conductance and the difference between action potential threshold and GABA reversal potential into account, resulted in a close correlation between calculated and experimentally obtained rheobase shifts. Addition of a linear term proportional to the GABAergic membrane depolarization improved the accuracy of correlation. The main advantage of using multiple linear regression with simple models is that direction and strength of GABAergic excitability shifts can be analyzed by using only measured parameters of GABAergic responses and with minimal a priori information about cellular parameters.

Electrophysiological and morphological properties of Cajal-Retzius cells with different ontogenetic origins.

The different origins of Cajal-Retzius cells (CRc) as well as their diverse molecular profile suggest that this cell type may represent different neuronal subpopulations. In order to investigate whether CRc from different origins show distinct functional or morphological characteristics we used transgenic Dbx1(cre);ROSA26(YFP) mice in which two subpopulations of CRc, originating from the septum and ventral pallium (VP) at the pallial-subpallial border (PSB), were permanently labeled by yellow fluorescent protein (YFP) expression. Electrophysiological properties of YFP(+) and YFP(-) CRc were investigated by whole-cell patch-clamp recordings, while a thorough somatodendritic and axonal reconstruction of the biocytin labeled CRc was subsequently performed using a Neurolucida system. Our experiments revealed that no significant differences in resting membrane potential, input resistance or capacitance, hyperpolarization activated currents and most action potentials properties could be observed between YFP(+) and YFP(-) CRc. Both YFP(+) and YFP(-) CRc displayed spontaneous and carbachol-induced GABAergic postsynaptic currents with similar properties and comparable NMDA-receptor mediated glutamatergic inward currents that were equally affected by the NR2B specific antagonist ifenprodil. Morphological reconstructions revealed that dendritic and axonal parameters are similar between YFP(+) and YFP(-) CRc, while the dendritic compartment of YFP(+) CRc was slightly larger. In summary, no considerable differences in functional and morphological properties between YFP(+) and YFP(-) CRc could be observed in this study. These observations suggest that CRc of different ontogenic origins display comparable functional properties in the early postnatal cortex and therefore perform similar functions within the transient neuronal networks of the developing cortex.

GABAC receptors are functionally expressed in the intermediate zone and regulate radial migration in the embryonic mouse neocortex.

Radial neuronal migration in the cerebral cortex depends on trophic factors and the activation of different voltage- and ligand-gated channels. To examine the functional role of GABA(C) receptors in radial migration we analyzed the effects of specific GABA(A) and GABA(C) receptor antagonists on the migration of BrdU-labeled neurons in vitro using organotypic neocortical slice cultures. These experiments revealed that the GABA(A) specific inhibitor bicuculline methiodide facilitated neuronal migration, while the GABA(C) specific inhibitor (1,2,5,6-tetrahydropyridine-4-yl) methylphosphinic-acid (TPMPA) impeded migration. Co-application of TPMPA and bicuculline methiodide or the unspecific ionotropic GABA receptor antagonist picrotoxin both impeded migration, suggesting that the GABA(C) receptor mediated effects dominate. Addition of the specific GABA(C) receptor agonist cis-4-aminocrotonic acid (CACA) also hampered migration, indicating that a physiological GABAergic stimulation is required for appropriate function. RT-PCR experiments using specific probes for GABA(C) receptor mRNA and Western blot assays using an antibody directed against rho subunits revealed the expression of GABA(C) receptor mRNA and translated GABA(C) receptor protein in the immature cortex. Microfluorimetric Ca(2+) imaging in neurons of identified cortical layers using Calcium Green revealed the functional expression of GABA(A) and GABA(C) receptors in the intermediate zone, while only GABA(A) receptor mediated responses were observed in the upper cortical plate. In summary, these results demonstrate that activation of GABA(C) receptors is a prerequisite for accurate migration and that GABA(C) receptors are functionally expressed in the intermediate zone.

Glycine receptors mediate excitation of subplate neurons in neonatal rat cerebral cortex.

The development of the cerebral cortex depends on genetic factors and early electrical activity patterns that form immature neuronal networks. Subplate neurons (SPn) are involved in the construction of thalamocortical innervation, generation of oscillatory network activity, and in the proper formation of the cortical columnar architecture. Because glycine receptors play an important role during early corticogenesis, we analyzed the functional consequences of glycine receptor activation in visually identified SPn in neocortical slices from postnatal day 0 (P0) to P4 rats using whole cell and perforated patch-clamp recordings. In all SPn the glycinergic agonists glycine, beta-alanine, and taurine induced dose-dependent inward currents with the affinity for glycine being higher than that for beta-alanine and taurine. Glycine-induced responses were blocked by the glycinergic antagonist strychnine, but were unaffected by either the GABAergic antagonist gabazine, the N-methyl-d-aspartate-receptor antagonist d-2-amino-5-phosphonopentanoic acid, or picrotoxin and cyanotriphenylborate, antagonists of alpha-homomeric and alpha1-subunit-containing glycine receptors, respectively. Under perforated-patch conditions, glycine induced membrane depolarizations that were sufficient to trigger action potentials (APs) in most cells. Furthermore, glycine and taurine decreased the injection currents as well as the synaptic stimulation strength required to elicit APs, indicating that glycine receptors have a consistent excitatory effect on SPn. Inhibition of taurine transport and application of hypoosmolar solutions induced strychnine-sensitive inward currents, suggesting that taurine can act as a possible endogenous agonist on SPn. In summary, these results demonstrate that SPn express glycine receptors that mediate robust excitatory membrane responses during early postnatal development.

Pathway-specificity in N-methyl-D-aspartate receptor-mediated synaptic inputs onto subplate neurons.

The subplate plays an important role in forming neuronal connections during early cortical development. We characterized by the use of whole-cell and cell-attached patch-clamp recordings in coronal brain slices from newborn mice (postnatal day [P] 0-3) the functional properties of two major pathways onto subplate neurons (SPn), the thalamocortical and the intra-subplate synaptic input. The two afferent pathways were stimulated extracellularly with bipolar electrodes placed in the thalamus and the subplate, respectively. Synaptically evoked and pharmacologically isolated N-methyl-d-aspartate receptor (NMDAR) -mediated responses with an onset latency of approximately 6 ms could be reliably recorded in P0-3 SPn. Whereas the intra-subplate input revealed a pronounced facilitation using paired pulse stimulation at 60-120 ms or repetitive activation at 10-40 Hz, the thalamocortical input was either stable or markedly suppressed under these conditions. Single cell reverse transcription PCR revealed the expression of the NR2A, B and D subunit in all investigated SPn. The intra-subplate and the thalamocortical synaptic input did not differ in their sensitivity to NVP-AAM077 or ifenprodil, indicating that both synaptic inputs have a similar NR2A/2B subunit composition. At P0, NMDAR-mediated synaptic inputs arising from the thalamus were significantly larger as compared with the intra-subplate input. This difference could no longer be detected in P2-3 SPn, indicating an input-specific developmental regulation during the first Ps. Our data indicate that the thalamocortical and intra-subplate synaptic input onto P0-3 SPn differs in functional, molecular and developmental properties. The intra-subplate synaptic input shows more mature functional properties and sustains high stimulation frequencies, thereby promoting the immature thalamocortical input to the developing neocortical circuit.

Model-specific effects of bumetanide on epileptiform activity in the in-vitro intact hippocampus of the newborn mouse.

The immature brain has a higher susceptibility to develop seizures, which often respond poorly to classical pharmacological treatment. It has been recently suggested that bumetanide, which blocks Na(+)-dependent K(+)-Cl(-)-cotransporter isoform 1 (NKCC1) and thus attenuates depolarizing GABAergic responses, could soothe epileptiform activity in immature nervous systems. To evaluate whether bumetanide consistently attenuates epileptiform activity, we investigated the effect of 10 microM bumetanide in five different in-vitro epilepsy models using field potential recordings in the CA3 region of intact mouse hippocampal preparations at postnatal day 4-7. Bumetanide reduced amplitude and frequency of ictal-like events (ILE) induced by 8.5 mM K(+), but it increased the frequency of ILE induced by 1 microM kainate. Inhibition of ligand-gated Cl(-) channels by 10 microM gabazine and 30 microM strychnine induced interictal activity (IA) that was only marginally affected by bumetanide. Removal of extracellular Mg(2+) induced both ILE and IA. Bumetanide had no effect on these ILE but enhanced the IA. Low-Mg(2+) solution containing 20 microM 4-AP induced late-recurrent discharges, which were slightly attenuated by bumetanide. In summary, our results demonstrate that bumetanide exerts diverse effects in different in-vitro epilepsy models.

Morphology, electrophysiology and functional input connectivity of pyramidal neurons characterizes a genuine layer va in the primary somatosensory cortex.

Cortical layer V classically has been subdivided into sublayers Va and Vb on cytoarchitectonic grounds. In the analysis of cortical microcircuits, however, layer Va has largely been ignored. The purpose of this study was to investigate pyramidal neurons of layer Va in view of their potential role in integrating information from lemniscal and paralemniscal sources. For this we combined detailed electrophysiological and morphological characterization with mapping of intracortical functional connectivity by caged glutamate photolysis in layer Va of rat barrel cortex in vitro. Electrophysiological characterization revealed pyramidal cells of the regular spiking as well as the intrinsically burst firing type. However, all layer Va pyramidal neurons displayed uniform morphological properties and comparable functional input connectivity patterns. They received most of their excitatory and inhibitory inputs from intracolumnar sources, especially from layer Va itself, but also from layer IV. Those two layers were also the main origin for transcolumnar excitatory inputs. Layer Va pyramidal neurons thus may predominantly integrate information intralaminarly as well as from layer IV. The functional connectivity maps clearly distinguish layer Va from layer Vb pyramidal cells, and suggest that layer Va plays a unique role in intracortical processing of sensory information.

CoCoDat: a database system for organizing and selecting quantitative data on single neurons and neuronal microcircuitry.

We present a novel database system for organizing and selecting quantitative experimental data on single neurons and neuronal microcircuitry that has proven useful for reference-keeping, experimental planning and computational modelling. Building on our previous experience with large neuroscientific databases, the system takes into account the diversity and method-dependence of single cell and microcircuitry data and provides tools for entering and retrieving published data without a priori interpretation or summarizing. Data representation is based on the framework suggested by biophysical theory and enables flexible combinations of data on membrane conductances, ionic and synaptic currents, morphology, connectivity and firing patterns. Innovative tools have been implemented for data retrieval with optional relaxation of search criteria along the conceptual dimensions of brain region, cortical layer, cell type and subcellular compartment. The relaxation procedures help to overcome the traditional trade-off between exact, non-interpreted data representation in the original nomenclature and convenient data retrieval. We demonstrate the use of these tools for the construction, tuning and validation of a multicompartmental model of a layer V pyramidal cell from the rat barrel cortex. CoCoDat is freely available at . Its application is scalable from offline use by individual researchers via local laboratory networks to a federation of distributed web sites in platform-independent XML format using Axiope tools.

Behavioural parameters in aged rats are related to LTP and gene expression of ChAT and NMDA-NR2 subunits in the striatum.

Striatal parameters were assessed for their relevance to age-related behavioural decline. Forty aged rats (28-30 months) were tested in the water maze and open field. Of these, seven superior and seven inferior learners were compared with each other in terms of levels of in vitro short- and long-term potentiation (STP and LTP), and gene expression of choline acetyltransferase (ChAT) as well as of the NMDA-NR2A-C subunits assessed by quantitative RT-PCR. Results revealed that the superior as compared with the inferior learners had higher levels of ChAT mRNA in the striatum. For the superior group, ChAT mRNA was correlated with escape on to the cued platform in the water maze, whereas level of LTP was predictive of place learning in the water maze and rearing activity in the open field. For the inferior group, expression of NR2A and NR2B was positively correlated with place learning and probe trial performance in the water maze. The results show that individual differences in various behaviours of aged rats were accounted for by variability in striatal parameters, i.e. LTP, ChAT and NMDA-NR2 subunit mRNA. Notably, the correlations found were heterogeneous amid the groups, e.g. variability in place learning was explained by variability in levels of LTP in the superior learners, but in levels of NR2A-B mRNA in the inferior group.

Homogenous glycine receptor expression in cortical plate neurons and Cajal-Retzius cells of neonatal rat cerebral cortex.

Glycinergic membrane responses have been described in cortical plate neurons (CPn) and Cajal-Retzius cells (CRc) during early neocortical development. In order to elucidate the functional properties and molecular identity of glycine receptors in these two neuronal cell types, we performed whole-cell patch-clamp recordings and subsequent single-cell multiplex reverse transcriptase-polymerase chain reaction (RT-PCR) analyses on visually identified neurons in tangential and coronal slices as well as in situ hybridizations of coronal slices from neonatal rat cerebral cortex (postnatal days 0-4). In both CPn and CRc the glycinergic agonists glycine, beta-alanine and taurine induced inward currents with larger current densities in CRc. The functional properties of these currents were similar between CPn and CRc. In both cell types the glycine receptor showed a higher affinity for glycine than for the glycinergic agonists beta-alanine and taurine. The glycinergic responses of both cells were blocked by the glycinergic antagonist strychnine and were unaffected by the GABAergic antagonist bicuculline (100 microM), the N-methyl-D-aspartic acid receptor antagonist (+/-)-2-amino-5-phosphonopentatonic acid (60 microM) and by picrotoxin (30 microM), an antagonist of alpha homomeric glycine receptors. Single-cell multiplex RT-PCR revealed the expression of glycine receptor alpha(2) and beta subunits in CPn and CRc, while no alpha(1) and alpha(3) subunits were observed. In situ hybridization histochemistry showed the expression of mRNAs for alpha(2) and beta subunits within the cortical plate and in large neurons of the marginal zone, while there were no signals for alpha(1) and alpha(3) subunits. In summary, these results suggest that CPn and CRc express glycine receptors with similar functional and pharmacological properties. The correlation of pharmacological properties and mRNA expression suggests that the glycine receptors in both cell types may consist of alpha(2)/beta heteromeric receptors.

Distribution of glutamate receptor subunits in experimentally induced cortical malformations.

Electrophysiological studies in humans and animal models have revealed an intrinsic epileptogenicity of cortical dysplasias which are a frequent cause of drug-resistant epilepsy. An imbalance of inhibition and excitation has been causative related. Receptor-binding studies in rodents demonstrated reduced binding to GABA and increased binding to glutamate receptors within cortical dysplasias and increments of AMPA- and kainate-receptor binding in its surround. Immunohistochemically a differential downregulation of GABA(A) receptor subunits could be demonstrated in widespread areas within and around dysplasias. As receptor binding critically depends on receptor subunit composition the observed changes in binding properties might be related to this. Here, we immunohistochemically analyzed the regional expression of four NMDA receptor subunits and two major AMPA- and kainate-receptor complexes in adult rats after neonatal freeze lesions. These lesions are characterized by a three- to four-layered cortex and a microsulcus which mimic human polymicrogyria. Using antibodies against NR1, NR2A, NR2B, NR2D, GluR2,3, and GluR5,6,7 receptor subunits we demonstrated a pronounced disturbance of cortical immunostaining pattern in the cortical malformation. These changes reflected the structural disorganization of the microgyrus with some distortion of the apical dendrites of paramicrogyral pyramidal cells, a decrease and disorganization of cells at the bottom of the microsulcus, and an inflection of apical dendrites toward the microsulcus. The neuronal staining pattern of large pyramidal cells in the neighborhood of the dysplasia did not differ for any subunit investigated. No remote or widespread changes of glutamate-receptor subunit distribution could be detected. The lack of gross and/or widespread alterations of glutamate-receptor subunit distribution in the surround of focal cortical dysplasia suggests the presence of other or additional mechanisms underlying the increased excitatory neurotransmitter binding and excitability in cortical malformations.

Water maze performance, exploratory activity, inhibitory avoidance and hippocampal plasticity in aged superior and inferior learners.

In 28- to 30-month-old rats, in vitro short-term and long-term potentiation (STP and LTP) were measured in area CA1 of the hippocampus in seven superior and seven inferior learners, that were selected from a pool of 40 rats based on water maze escape performance over a period of 9 days. The aim was to examine whether levels of STP and LTP could account for group differences in learning of water maze escape, spatial preference and wall (thigmotaxis)-avoidance and in short-term retention of an inhibitory avoidance task. There was no significant group difference in open-field exploration, i.e. the number of rearings. In contrast to expectation, the superior and inferior learners did not differ significantly from each other in levels of STP and LTP. However, variability in escape and spatial learning, but not thigmotaxis-avoidance learning, was significantly predicted by variability in STP and LTP in the superior group. Also, open-field exploratory rearings were significantly correlated with STP and LTP as well as with maze escape learning in the superior group. The results show that, in the aged superior group, levels of CA1 STP and LTP coincided with residual water maze escape and spatial preference learning as well as open-field exploration, i.e. behavioural expressions known to be related to hippocampal functioning, but not with learning to avoid thigmotaxis in the maze. The lack of such correlations in the inferior group may be due to the severe impairment in escape and spatial preference learning and/or the influence of yet unknown third variables on these relationships.

Depolarizing glycine responses in Cajal-Retzius cells of neonatal rat cerebral cortex.

We investigated the properties of glycine-induced responses in Cajal-Retzius cells, a neuronal cell type essential for the establishment of neocortical lamination. Whole-cell and gramicidin-perforated patch-clamp recordings were performed on visually identified Cajal-Retzius cells in tangential slices from neonatal rat cortex (postnatal days 0-3). With a pipette Cl(-) concentration of 50 mM, bath application of 1 mM glycine induced a membrane depolarization of 32.8+/-7.4 mV and a massive decrease in membrane resistance by 88+/-1.4%. The membrane depolarization was abolished in the presence of the glycinergic antagonists strychnine (30 microM) and phenylbenzene-omega-phosphono-alpha-amino acid (100 microM), while the GABA(A) receptor antagonist bicuculline (100 microM) and the glutamatergic antagonist (+/-)-2-amino-5-phosphonopentatonic acid (60 microM) were without effect, suggesting that the glycine-induced membrane responses were mediated exclusively by the strychnine-sensitive glycine receptor. The EC(50) for activation of glycine receptors was 0.54 mM, 1.62 mM and 2.41 mM, for the glycinergic agonists glycine, beta-alanine and taurine, respectively. Since the reversal potential of the glycine-induced currents showed a strong dependency on the intracellular chloride concentration and was virtually unaffected under HCO(3)(-)-free conditions, the activation of glycine receptors was probably linked to Cl(-) fluxes with little contribution of HCO(3)(-) ions. Perforated patch recordings from Cajal-Retzius cells demonstrated that glycine elicited depolarizing responses mediated by Cl(-) currents which reversed at -41+/-3.7 mV. In summary, from these results we suggest that Cajal-Retzius cells of the neonatal rat cerebral cortex express functional strychnine-sensitive glycine receptors that mediate depolarizing membrane responses via Cl(-) efflux.

Epileptiform activity in a neocortical network: a mathematical model.

A simple mathematical model describing the generation and propagation of epileptiform activity in a cerebral cortical network is presented. The model consists of a system of nonlinear delay differential equations. Physiological properties are taken into account as nonlinear transmission of signals at the synapse, temporal and spatial summation of incoming signals at the soma, active membrane characteristics, and dendritic and axonal propagation times. The influence of the connectivity and the temporal parameters on the oscillatory properties of the model is studied. The computer simulations are in agreement with experimental observations in cortical networks: whereas a weak excitatory or strong inhibitory synaptic connection strength produces a stationary status with short-lasting responses to external stimuli, increases in excitation or decreases in inhibition induce spontaneous and stimulus-evoked rhythmic discharges. Synaptic burst-like activity is observed only for an intermediate range of excitatory and inhibitory connection strengths and external inputs. The form and duration of the bursts can also be controlled by the temporal parameters. The results demonstrate that relatively simple mathematical equations are sufficient to model some of the network properties underlying the generation and propagation of epileptiform activity.