Modelling the spatial and temporal constrains of the GABAergic influence on neuronal excitability.

GABA (γ-amino butyric acid) is an inhibitory neurotransmitter in the adult brain that can mediate depolarizing responses during development or after neuropathological insults. Under which conditions GABAergic membrane depolarizations are sufficient to impose excitatory effects is hard to predict, as shunting inhibition and GABAergic effects on spatiotemporal filtering of excitatory inputs must be considered. To evaluate at which reversal potential a net excitatory effect was imposed by GABA (EGABAThr), we performed a detailed in-silico study using simple neuronal topologies and distinct spatiotemporal relations between GABAergic and glutamatergic inputs. These simulations revealed for GABAergic synapses located at the soma an EGABAThr close to action potential threshold (EAPThr), while with increasing dendritic distance EGABAThr shifted to positive values. The impact of GABA on AMPA-mediated inputs revealed a complex temporal and spatial dependency. EGABAThr depends on the temporal relation between GABA and AMPA inputs, with a striking negative shift in EGABAThr for AMPA inputs appearing after the GABA input. The spatial dependency between GABA and AMPA inputs revealed a complex profile, with EGABAThr being shifted to values negative to EAPThr for AMPA synapses located proximally to the GABA input, while for distally located AMPA synapses the dendritic distance had only a minor effect on EGABAThr. For tonic GABAergic conductances EGABAThr was negative to EAPThr over a wide range of gGABAtonic values. In summary, these results demonstrate that for several physiologically relevant situations EGABAThr is negative to EAPThr, suggesting that depolarizing GABAergic responses can mediate excitatory effects even if EGABA did not reach EAPThr.

Coincident glutamatergic depolarizations enhance GABAA receptor-dependent Cl- influx in mature and suppress Cl- efflux in immature neurons.

The impact of GABAergic transmission on neuronal excitability depends on the Cl--gradient across membranes. However, the Cl--fluxes through GABAA receptors alter the intracellular Cl- concentration ([Cl-]i) and in turn attenuate GABAergic responses, a process termed ionic plasticity. Recently it has been shown that coincident glutamatergic inputs significantly affect ionic plasticity. Yet how the [Cl-]i changes depend on the properties of glutamatergic inputs and their spatiotemporal relation to GABAergic stimuli is unknown. To investigate this issue, we used compartmental biophysical models of Cl- dynamics simulating either a simple ball-and-stick topology or a reconstructed CA3 neuron. These computational experiments demonstrated that glutamatergic co-stimulation enhances GABA receptor-mediated Cl- influx at low and attenuates or reverses the Cl- efflux at high initial [Cl-]i. The size of glutamatergic influence on GABAergic Cl--fluxes depends on the conductance, decay kinetics, and localization of glutamatergic inputs. Surprisingly, the glutamatergic shift in GABAergic Cl--fluxes is invariant to latencies between GABAergic and glutamatergic inputs over a substantial interval. In agreement with experimental data, simulations in a reconstructed CA3 pyramidal neuron with physiological patterns of correlated activity revealed that coincident glutamatergic synaptic inputs contribute significantly to the activity-dependent [Cl-]i changes. Whereas the influence of spatial correlation between distributed glutamatergic and GABAergic inputs was negligible, their temporal correlation played a significant role. In summary, our results demonstrate that glutamatergic co-stimulation had a substantial impact on ionic plasticity of GABAergic responses, enhancing the attenuation of GABAergic inhibition in the mature nervous systems, but suppressing GABAergic [Cl-]i changes in the immature brain. Therefore, glutamatergic shift in GABAergic Cl--fluxes should be considered as a relevant factor of short-term plasticity.

GABA Release from Astrocytes in Health and Disease.

Astrocytes are the most abundant glial cells in the central nervous system (CNS) mediating a variety of homeostatic functions, such as spatial K+ buffering or neurotransmitter reuptake. In addition, astrocytes are capable of releasing several biologically active substances, including glutamate and GABA. Astrocyte-mediated GABA release has been a matter of debate because the expression level of the main GABA synthesizing enzyme glutamate decarboxylase is quite low in astrocytes, suggesting that low intracellular GABA concentration ([GABA]i) might be insufficient to support a non-vesicular GABA release. However, recent studies demonstrated that, at least in some regions of the CNS, [GABA]i in astrocytes might reach several millimoles both under physiological and especially pathophysiological conditions, thereby enabling GABA release from astrocytes via GABA-permeable anion channels and/or via GABA transporters operating in reverse mode. In this review, we summarize experimental data supporting both forms of GABA release from astrocytes in health and disease, paying special attention to possible feedback mechanisms that might govern the fine-tuning of astrocytic GABA release and, in turn, the tonic GABAA receptor-mediated inhibition in the CNS.

Gadd45α modulates aversive learning through post-transcriptional regulation of memory-related mRNAs.

Learning is essential for survival and is controlled by complex molecular mechanisms including regulation of newly synthesized mRNAs that are required to modify synaptic functions. Despite the well-known role of RNA-binding proteins (RBPs) in mRNA functionality, their detailed regulation during memory consolidation is poorly understood. This study focuses on the brain function of the RBP Gadd45α (growth arrest and DNA damage-inducible protein 45 alpha, encoded by the Gadd45a gene). Here, we find that hippocampal memory and long-term potentiation are strongly impaired in Gadd45a-deficient mice, a phenotype accompanied by reduced levels of memory-related mRNAs. The majority of the Gadd45α-regulated transcripts show unusually long 3' untranslated regions (3'UTRs) that are destabilized in Gadd45a-deficient mice via a transcription-independent mechanism, leading to reduced levels of the corresponding proteins in synaptosomes. Moreover, Gadd45α can bind specifically to these memory-related mRNAs. Our study reveals a new function for extended 3'UTRs in memory consolidation and identifies Gadd45α as a novel regulator of mRNA stability.

Optogenetically Controlled Activity Pattern Determines Survival Rate of Developing Neocortical Neurons.

A substantial proportion of neurons undergoes programmed cell death (apoptosis) during early development. This process is attenuated by increased levels of neuronal activity and enhanced by suppression of activity. To uncover whether the mere level of activity or also the temporal structure of electrical activity affects neuronal death rates, we optogenetically controlled spontaneous activity of synaptically-isolated neurons in developing cortical cultures. Our results demonstrate that action potential firing of primary cortical neurons promotes neuronal survival throughout development. Chronic patterned optogenetic stimulation allowed to effectively modulate the firing pattern of single neurons in the absence of synaptic inputs while maintaining stable overall activity levels. Replacing the burst firing pattern with a non-physiological, single pulse pattern significantly increased cell death rates as compared to physiological burst stimulation. Furthermore, physiological burst stimulation led to an elevated peak in intracellular calcium and an increase in the expression level of classical activity-dependent targets but also decreased Bax/BCL-2 expression ratio and reduced caspase 3/7 activity. In summary, these results demonstrate at the single-cell level that the temporal pattern of action potentials is critical for neuronal survival versus cell death fate during cortical development, besides the pro-survival effect of action potential firing per se.

Taurine potentiates the anticonvulsive effect of the GABAA agonist muscimol and pentobarbital in the immature mouse hippocampus.

OBJECTIVE: The high incidence of epileptic seizures in neonates and their frequent refractoriness to pharmacologic therapies require identification of new therapeutical options. Therefore, we investigated whether the modulatory effect of taurine on γ-aminobutyric acid (GABA)A receptors can enhance the anticonvulsive potential of the GABAA receptor agonist muscimol and of the barbiturate pentobarbital. METHODS: We performed field potential recordings in in toto hippocampus preparations of immature (postnatal days 4-7) C57Bl/6 mouse pups. Spontaneous epileptiform activity was induced by the continuous presence of the potassium channel blocker 4-aminopyridine and the glycinergic antagonist strychnine in Mg2+ -free solutions. RESULTS: Bath application of 0.1 µmol/L muscimol increases the occurrence of recurrent epileptiform discharges, whereas they are significantly attenuated in a dose-dependent manner by muscimol in concentrations between 0.5 and 5 µmol/L. Taurine at concentrations between 0.1 and 0.5 mmol/L induces a proconvulsive effect, but upon coapplication, it significantly augments the anticonvulsive effect of moderate muscimol doses (0.5-1 µmol/L). In addition, the anticonvulsive effect of 100 and 200 µmol/L pentobarbital is increased significantly in the presence of 0.5 µmol/L taurine. SIGNIFICANCE: These observations demonstrate that taurine can indeed enhance the anticonvulsive effects of muscimol and pentobarbital, suggesting that taurine may act as a positive modulator on GABAA receptors. Thus, interfering with the modulatory taurine binding site of GABAA receptors or the interstitial taurine concentration may provide new therapeutical options for anticonvulsive therapies in neonates.

Autism Related Neuroligin-4 Knockout Impairs Intracortical Processing but not Sensory Inputs in Mouse Barrel Cortex.

Neuroligin-4 (Nlgn4) is a cell adhesion protein that regulates synapse organization and function. Mutations in human NLGN4 are among the causes of autism spectrum disorders. In mouse, Nlgn4 knockout (KO) perturbs GABAergic synaptic transmission and oscillatory activity in hippocampus, and causes social interaction deficits. The complex profile of cellular and circuit changes that are caused by Nlgn4-KO is still only partly understood. Using Nlgn4-KO mice, we found that Nlgn4-KO increases the power in the alpha frequency band of spontaneous network activity in the barrel cortex under urethane anesthesia in vivo. Nlgn4-KO did not affect single-whisker-induced local field potentials, but suppressed the late evoked multiunit activity in vivo. Although Nlgn4-KO did not affect evoked EPSCs in layer 4 (L4) spiny stellate cells in acute thalamocortical slices elicited by electrical stimulation of thalamocortical inputs, it caused a lower frequency of both miniature (m) IPSCs and mEPSCs, and a decrease in the number of readily releasable vesicles at GABAergic and glutamatergic connections, weakening both excitatory and inhibitory transmission. However, Nlgn4 deficit strongly suppresses glutamatergic activity, shifting the excitation-inhibition balance to inhibition. We conclude that Nlgn4-KO does not influence the incoming whisker-mediated sensory information to the barrel cortex, but modifies intracortical information processing.

Interactions between Membrane Resistance, GABA-A Receptor Properties, Bicarbonate Dynamics and Cl--Transport Shape Activity-Dependent Changes of Intracellular Cl- Concentration.

The effects of ionotropic γ-aminobutyric acid receptor (GABA-A, GABAA) activation depends critically on the Cl--gradient across neuronal membranes. Previous studies demonstrated that the intracellular Cl--concentration ([Cl-]i) is not stable but shows a considerable amount of activity-dependent plasticity. To characterize how membrane properties and different molecules that are directly or indirectly involved in GABAergic synaptic transmission affect GABA-induced [Cl-]i changes, we performed compartmental modeling in the NEURON environment. These simulations demonstrate that GABA-induced [Cl-]i changes decrease at higher membrane resistance, revealing a sigmoidal dependency between both parameters. Increase in GABAergic conductivity enhances [Cl-]i with a logarithmic dependency, while increasing the decay time of GABAA receptors leads to a nearly linear enhancement of the [Cl-]i changes. Implementing physiological levels of HCO3--conductivity to GABAA receptors enhances the [Cl-]i changes over a wide range of [Cl-]i, but this effect depends on the stability of the HCO3- gradient and the intracellular pH. Finally, these simulations show that pure diffusional Cl--elimination from dendrites is slow and that a high activity of Cl--transport is required to improve the spatiotemporal restriction of GABA-induced [Cl-]i changes. In summary, these simulations revealed a complex interplay between several key factors that influence GABA-induced [Cl]i changes. The results suggest that some of these factors, including high resting [Cl-]i, high input resistance, slow decay time of GABAA receptors and dynamic HCO3- gradient, are specifically adapted in early postnatal neurons to facilitate limited activity-dependent [Cl-]i decreases.

Neocortical Layer 6B as a Remnant of the Subplate - A Morphological Comparison.

The fate of the subplate (SP) is still a matter of debate. The SP and layer 6 (which is ontogenetically the oldest and innermost neocortical lamina) develop coincidentally. Yet, the function of sublamina 6B is largely unknown. It has been suggested that it consists partly of neurons from the transient SP, however, experimental evidence for this hypothesis is still missing. To obtain first insights into the neuronal complement of layer 6B in the somatosensory rat barrel cortex, we used biocytin stainings of SP neurons (aged 0-4 postnatal days, PND) and layer 6B neurons (PND 11-35) obtained during in vitro whole-cell patch-clamp recordings. Neurons were reconstructed for a quantitative characterization of their axonal and dendritic morphology. An unsupervised cluster analysis revealed that the SP and layer 6B consist of heterogeneous but comparable neuronal cell populations. Both contain 5 distinct spine-bearing cell types whose relative fractions change with increasing age. Pyramidal cells were more prominent in layer 6B, whereas non-pyramidal neurons were less frequent. Because of the high morphological similarity of SP and layer 6B neurons, we suggest that layer 6B consists of persistent non-pyramidal neurons from the SP and cortical L6B pyramidal neurons.

Putative Role of Taurine as Neurotransmitter During Perinatal Cortical Development.

Neurotransmitters and neuronal activity affect neurodevelopmental events like neurogenesis, neuronal migration, apoptosis and differentiation. Beside glutamate and gamma-amino butyric acid, the aminosulfonic acid taurine has been considered as possible neurotransmitter that influences early neuronal development. In this article I review recent studies of our group which demonstrate that taurine can affect a variety of identified neuronal populations in the immature neocortex and directly modulates neuronal activity. These experiments revealed that taurine evoke dose-dependent membrane responses in a variety of neocortical neuron populations, including Cajal-Retzius cells, subplate neurons and GABAergic interneurons. Taurine responses persist in the presence of GABA(A) receptor antagonists and are reduced by the addition of strychnine, suggesting that glycine receptors are involved in taurine-mediated membrane responses. Gramicidin-perforated patch-clamp and cell-attached recordings demonstrated that taurine evokes depolarizing and mainly excitatory membrane responses, in accordance with the high intracellular Cl- concentration in immature neurons. In addition, taurine increases the frequency of postsynaptic GABAergic currents (PSCs) in a considerable fraction of immature pyramidal neurons, indicating a specific activation of presynaptic GABAergic networks projecting toward and exciting pyramidal neurons. In summary, these results suggest that taurine may be critically involved in the regulation of network excitability in the immature neocortex and hippocampus via interactions with glycine receptors.

High Stimulus-Related Information in Barrel Cortex Inhibitory Interneurons.

The manner in which populations of inhibitory (INH) and excitatory (EXC) neocortical neurons collectively encode stimulus-related information is a fundamental, yet still unresolved question. Here we address this question by simultaneously recording with large-scale multi-electrode arrays (of up to 128 channels) the activity of cell ensembles (of up to 74 neurons) distributed along all layers of 3-4 neighboring cortical columns in the anesthetized adult rat somatosensory barrel cortex in vivo. Using two different whisker stimulus modalities (location and frequency) we show that individual INH neurons--classified as such according to their distinct extracellular spike waveforms--discriminate better between restricted sets of stimuli (≤6 stimulus classes) than EXC neurons in granular and infra-granular layers. We also demonstrate that ensembles of INH cells jointly provide as much information about such stimuli as comparable ensembles containing the ~20% most informative EXC neurons, however presenting less information redundancy - a result which was consistent when applying both theoretical information measurements and linear discriminant analysis classifiers. These results suggest that a consortium of INH neurons dominates the information conveyed to the neocortical network, thereby efficiently processing incoming sensory activity. This conclusion extends our view on the role of the inhibitory system to orchestrate cortical activity.

Laminar and Columnar Structure of Sensory-Evoked Multineuronal Spike Sequences in Adult Rat Barrel Cortex In Vivo.

One of the most relevant questions regarding the function of the nervous system is how sensory information is represented in populations of cortical neurons. Despite its importance, the manner in which sensory-evoked activity propagates across neocortical layers and columns has yet not been fully characterized. In this study, we took advantage of the distinct organization of the rodent barrel cortex and recorded with multielectrode arrays simultaneously from up to 74 neurons localized in several functionally identified layers and columns of anesthetized adult Wistar rats in vivo. The flow of activity within neuronal populations was characterized by temporally precise spike sequences, which were repeatedly evoked by single-whisker stimulation. The majority of the spike sequences representing instantaneous responses were led by a subgroup of putative inhibitory neurons in the principal column at thalamo-recipient layers, thus revealing the presence of feedforward inhibition. However, later spike sequences were mainly led by infragranular excitatory neurons in neighboring columns. Although the starting point of the sequences was anatomically confined, their ending point was rather scattered, suggesting that the population responses are structurally dispersed. Our data show for the first time the simultaneous intra- and intercolumnar processing of information at high temporal resolution.

Spindle Bursts in Neonatal Rat Cerebral Cortex.

Spontaneous and sensory evoked spindle bursts represent a functional hallmark of the developing cerebral cortex in vitro and in vivo. They have been observed in various neocortical areas of numerous species, including newborn rodents and preterm human infants. Spindle bursts are generated in complex neocortical-subcortical circuits involving in many cases the participation of motor brain regions. Together with early gamma oscillations, spindle bursts synchronize the activity of a local neuronal network organized in a cortical column. Disturbances in spindle burst activity during corticogenesis may contribute to disorders in cortical architecture and in the activity-dependent control of programmed cell death. In this review we discuss (i) the functional properties of spindle bursts, (ii) the mechanisms underlying their generation, (iii) the synchronous patterns and cortical networks associated with spindle bursts, and (iv) the physiological and pathophysiological role of spindle bursts during early cortical development.

Sensory-evoked and spontaneous gamma and spindle bursts in neonatal rat motor cortex.

Self-generated neuronal activity originating from subcortical regions drives early spontaneous motor activity, which is a hallmark of the developing sensorimotor system. However, the neural activity patterns and role of primary motor cortex (M1) in these early movements are still unknown. Combining voltage-sensitive dye imaging (VSDI) with simultaneous extracellular multielectrode recordings in postnatal day 3 (P3)-P5 rat primary somatosensory cortex (S1) and M1 in vivo, we observed that tactile forepaw stimulation induced spindle bursts in S1 and gamma and spindle bursts in M1. Approximately 40% of the spontaneous gamma and spindle bursts in M1 were driven by early motor activity, whereas 23.7% of the M1 bursts triggered forepaw movements. Approximately 35% of the M1 bursts were uncorrelated to movements and these bursts had significantly fewer spikes and shorter burst duration. Focal electrical stimulation of layer V neurons in M1 mimicking physiologically relevant 40 Hz gamma or 10 Hz spindle burst activity reliably elicited forepaw movements. We conclude that M1 is already involved in somatosensory information processing during early development. M1 is mainly activated by tactile stimuli triggered by preceding spontaneous movements, which reach M1 via S1. Only a fraction of M1 activity transients trigger motor responses directly. We suggest that both spontaneously occurring and sensory-evoked gamma and spindle bursts in M1 contribute to the maturation of corticospinal and sensorimotor networks required for the refinement of sensorimotor coordination.

Activation of glycine receptors modulates spontaneous epileptiform activity in the immature rat hippocampus.

While the expression of glycine receptors in the immature hippocampus has been shown, no information about the role of glycine receptors in controlling the excitability in the immature CNS is available. Therefore, we examined the effect of glycinergic agonists and antagonists in the CA3 region of an intact corticohippocampal preparation of the immature (postnatal days 4-7) rat using field potential recordings. Bath application of 100 µM taurine or 10 µM glycine enhanced the occurrence of recurrent epileptiform activity induced by 20 µM 4-aminopyridine in low Mg(2+) solution. This proconvulsive effect was prevented by 3 µM strychnine or after incubation with the loop diuretic bumetanide (10 µM), suggesting that it required glycine receptors and an active NKCC1-dependent Cl(-) accumulation. Application of higher doses of taurine (≥ 1 mM) or glycine (100 µM) attenuated recurrent epileptiform discharges. The anticonvulsive effect of taurine was also observed in the presence of the GABAA receptor antagonist gabazine and was attenuated by strychnine, suggesting that it was partially mediated by glycine receptors. Bath application of the glycinergic antagonist strychnine (0.3 µM) induced epileptiform discharges. We conclude from these results that in the immature hippocampus, activation of glycine receptors can mediate both pro- and anticonvulsive effects, but that a persistent activation of glycine receptors is required to suppress epileptiform activity. In summary, our study elucidated the important role of glycine receptors in the control of neuronal excitability in the immature hippocampus.

Thalamic network oscillations synchronize ontogenetic columns in the newborn rat barrel cortex.

Neocortical areas are organized in columns, which form the basic structural and functional modules of intracortical information processing. Using voltage-sensitive dye imaging and simultaneous multi-channel extracellular recordings in the barrel cortex of newborn rats in vivo, we found that spontaneously occurring and whisker stimulation-induced gamma bursts followed by longer lasting spindle bursts were topographically organized in functional cortical columns already at the day of birth. Gamma bursts synchronized a cortical network of 300-400 µm in diameter and were coherent with gamma activity recorded simultaneously in the thalamic ventral posterior medial (VPM) nucleus. Cortical gamma bursts could be elicited by focal electrical stimulation of the VPM. Whisker stimulation-induced spindle and gamma bursts and the majority of spontaneously occurring events were profoundly reduced by the local inactivation of the VPM, indicating that the thalamus is important to generate these activity patterns. Furthermore, inactivation of the barrel cortex with lidocaine reduced the gamma activity in the thalamus, suggesting that a cortico-thalamic feedback loop modulates this early thalamic network activity.

Long-term potentiation in the neonatal rat barrel cortex in vivo.

Long-term potentiation (LTP) is important for the activity-dependent formation of early cortical circuits. In the neonatal rodent barrel cortex, LTP has been studied only in vitro. We combined voltage-sensitive dye imaging with extracellular multielectrode recordings to study whisker stimulation-induced LTP in the whisker-to-barrel cortex pathway of the neonatal rat barrel cortex in vivo. Single whisker stimulation at 2 Hz for 10 min induced an age-dependent expression of LTP in postnatal day (P) 0 to P14 rats, with the strongest expression of LTP at P3-P5. The magnitude of LTP was largest in the activated barrel-related column, smaller in the surrounding septal region, and no LTP could be observed in the neighboring barrel. Current source density analyses revealed an LTP-associated increase of synaptic current sinks in layer IV/lower layer II/III at P3-P5 and in the cortical plate/upper layer V at P0-P1. Our study demonstrates for the first time an age-dependent and spatially confined LTP in the barrel cortex of the newborn rat in vivo.

Axonal connections between S1 barrel, M1, and S2 cortex in the newborn mouse.

The development of functionally interconnected networks between primary (S1), secondary somatosensory (S2), and motor (M1) cortical areas requires coherent neuronal activity via corticocortical projections. However, the anatomical substrate of functional connections between S1 and M1 or S2 during early development remains elusive. In the present study, we used ex vivo carbocyanine dye (DiI) tracing in paraformaldehyde-fixed newborn mouse brain to investigate axonal projections of neurons in different layers of S1 barrel field (S1Bf), M1, and S2 toward the subplate (SP), a hub layer for sensory information transfer in the immature cortex. In addition, we performed extracellular recordings in neocortical slices to unravel the functional connectivity between these areas. Our experiments demonstrate that already at P0 neurons from the cortical plate (CP), layer 5/6 (L5/6), and the SP of both M1 and S2 send projections through the SP of S1Bf. Reciprocally, neurons from CP to SP of S1Bf send projections through the SP of M1 and S2. Electrophysiological recordings with multi-electrode arrays in cortical slices revealed weak, but functional synaptic connections between SP and L5/6 within and between S1 and M1. An even lower functional connectivity was observed between S1 and S2. In summary, our findings demonstrate that functional connections between SP and upper cortical layers are not confined to the same cortical area, but corticocortical connection between adjacent cortical areas exist already at the day of birth. Hereby, SP can integrate early cortical activity of M1, S1, and S2 and shape the development of sensorimotor integration at an early stage.

Recovery kinetics of short-term depression of GABAergic and glutamatergic synapses at layer 2/3 pyramidal cells in the mouse barrel cortex.

Introduction: Short-term synaptic plasticity (STP) is a widespread mechanism underlying activity-dependent modifications of cortical networks. Methods: To investigate how STP influences excitatory and inhibitory synapses in layer 2/3 of mouse barrel cortex, we combined whole-cell patch-clamp recordings from visually identified pyramidal neurons (PyrN) and parvalbumin-positive interneurons (PV-IN) of cortical layer 2/3 in acute slices with electrical stimulation of afferent fibers in layer 4 and optogenetic activation of PV-IN. Results: These experiments revealed that electrical burst stimulation (10 pulses at 10 Hz) of layer 4 afferents to layer 2/3 neurons induced comparable short-term depression (STD) of glutamatergic postsynaptic currents (PSCs) in PyrN and in PV-IN, while disynaptic GABAergic PSCs in PyrN showed a stronger depression. Burst-induced depression of glutamatergic PSCs decayed within <4 s, while the decay of GABAergic PSCs required >11 s. Optogenetically-induced GABAergic PSCs in PyrN also demonstrated STD after burst stimulation, with a decay of >11 s. Excitatory postsynaptic potentials (EPSPs) in PyrN were unaffected after electrical burst stimulation, while a selective optogenetic STD of GABAergic synapses caused a transient increase of electrically evoked EPSPs in PyrN. Discussion: In summary, these results demonstrate substantial short-term plasticity at all synapses investigated and suggest that the prominent STD observed in GABAergic synapses can moderate the functional efficacy of glutamatergic STD after repetitive synaptic stimulations. This mechanism may contribute to a reliable information flow toward the integrative layer 2/3 for complex time-varying sensory stimuli.

Resonance properties of different neuronal populations in the immature mouse neocortex.

In vivo recordings in the immature neocortex revealed spontaneous and sensory-driven oscillatory activity from delta (0.5-4 Hz) to gamma (30-100 Hz) frequencies. In order to investigate whether the resonance properties of distinct neuronal populations in the immature neocortex contribute to these network oscillations, we performed whole-cell patch-clamp recordings from visually identified neurons in tangential and coronal neocortical slices from postnatal day (P)0-P7 C57Bl/6 mice. Subthreshold resonance was analysed by sinusoidal current injection of varying frequency. All Cajal-Retzius cells showed subthreshold resonance, with an average frequency of 2.6 ± 0.1 Hz (n = 60), which was massively reduced by ZD7288, a blocker of hyperpolarization-activated cation currents. Approximately 65.6% (n = 61) of the supragranular pyramidal neurons showed subthreshold resonance, with an average frequency of 1.4 ± 0.1 Hz (n = 40). Application of Ni(2+) suppressed subthreshold resonance, suggesting that low-threshold calcium currents contribute to resonance in these neurons. Approximately 63.6% (n = 77) of the layer V pyramidal neurons showed subthreshold resonance, with an average frequency of 1.4 ± 0.2 Hz (n = 49), which was abolished by ZD7288. Only 44.1% (n = 59) of the subplate neurons showed subthreshold resonance, with an average frequency of 1.3 ± 0.2 Hz (n = 26) and a small resonance strength. In summary, these results demonstrate that neurons in all investigated layers show resonance behavior, with either hyperpolarization-activated cation or low-threshold calcium currents contributing to the subthreshold resonance. The observed resonance frequencies are in the range of slow activity patterns observed in the immature neocortex, suggesting that subthreshold resonance may support the generation of this activity.