Membrane Potential Dynamics of GABAergic Neurons in the Barrel Cortex of Behaving Mice

Laboratory of Sensory Processing, Brain Mind Institute, Faculty of Life Sciences, Ecole Polytechnique Fédérale de Lausanne, CH-1015 Lausanne, Switzerland.
Neuron (Impact Factor: 15.98). 02/2010; 65(3):422-35. DOI: 10.1016/j.neuron.2010.01.006
Source: PubMed

ABSTRACT Computations in cortical circuits are mediated by synaptic interactions between excitatory and inhibitory neurons, and yet we know little about their activity in awake animals. Here, through single and dual whole-cell recordings combined with two-photon microscopy in the barrel cortex of behaving mice, we directly compare the synaptically driven membrane potential dynamics of inhibitory and excitatory layer 2/3 neurons. We find that inhibitory neurons depolarize synchronously with excitatory neurons, but they are much more active with differential contributions of two classes of inhibitory neurons during different brain states. Fast-spiking GABAergic neurons dominate during quiet wakefulness, but during active wakefulness Non-fast-spiking GABAergic neurons depolarize, firing action potentials at increased rates. Sparse uncorrelated action potential firing in excitatory neurons is driven by fast, large, and cell-specific depolarization. In contrast, inhibitory neurons fire correlated action potentials at much higher frequencies driven by slower, smaller, and broadly synchronized depolarization.

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Available from: Luc J Gentet, Jul 17, 2015
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    • "Also, whisker-evoked responses are a product of complex interactions between cortical and subcortical brain structures, being highly dependent on stimulus timing and strength and on the state of vigilance of the animal. Thus it is conceivable that subtle alterations might not be detectable by a simple analysis of response amplitudes (Gentet et al., 2010). Furthermore we hypothesized that the increased response variance seen in the VSD recordings of whiskerevoked responses might be related to altered spontaneous cortical activity . "
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    Neurobiology of Disease 02/2015; 77. DOI:10.1016/j.nbd.2015.02.018 · 5.20 Impact Factor
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    • "As a consequence, one predicts a smaller rise of the intraterminal basal [Ca] in in cortical excitatory terminals than measured in SL/SL Calyx terminals (Di Guilmi et al., 2014); this probably explains why the mechanism of facilitation of release (independent of Ca 2+ influx and dependent on increased basal [Ca] in ) that has been proposed to underlie the gain-of-function of AP-evoked glutamate release in Calyx (Di Guilmi et al., 2014), does not appear to contribute to the gain-of-function of excitatory transmission at SL/SL cortical pyramidal cell synapses. Nonetheless, since V resting of cortical pyramidal cells in vivo in awake animals and also in sleeping or anesthetized animals during the up-states is 10–20 mV more depolarized than that in acute cortical slices (Gentet et al., 2010; Mateo et al., 2011), the fraction of open mutant Ca V 2.1 channels and the rise of basal [Ca] in might be larger in S218L KI mice in vivo. "
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    ABSTRACT: Familial hemiplegic migraine type 1 (FHM1) is caused by gain-of-function mutations in CaV2.1 (P/Q-type) Ca(2+) channels. Knockin (KI) mice carrying the FHM1 R192Q missense mutation show enhanced cortical excitatory synaptic transmission at pyramidal cell synapses but unaltered cortical inhibitory neurotransmission at fast-spiking interneuron synapses. Enhanced cortical glutamate release was shown to cause the facilitation of cortical spreading depression (CSD) in R192Q KI mice. It, however, remains unknown how other FHM1 mutations affect cortical synaptic transmission. Here, we studied neurotransmission in cortical neurons in microculture from KI mice carrying the S218L mutation, which causes a severe FHM syndrome in humans and an allele-dosage dependent facilitation of experimental CSD in KI mice, which is larger than that caused by the R192Q mutation. We show gain-of-function of excitatory neurotransmission, due to increased action-potential evoked Ca(2+) influx and increased probability of glutamate release at pyramidal cell synapses, but unaltered inhibitory neurotransmission at multipolar interneuron synapses in S218L KI mice. In contrast with the larger gain-of-function of neuronal CaV2.1 current in homozygous than heterozygous S218L KI mice, the gain-of-function of evoked glutamate release, the paired-pulse ratio and the Ca(2+) dependence of the excitatory postsynaptic current were similar in homozygous and heterozygous S218L KI mice, suggesting compensatory changes in the homozygous mice. Furthermore, we reveal a unique feature of S218L KI cortical synapses which is the presence of a fraction of mutant CaV2.1 channels being open at resting potential. Our data suggest that, while the gain-of-function of evoked glutamate release may explain the facilitation of CSD in heterozygous S218L KI mice, the further facilitation of CSD in homozygous S218L KI mice is due to other CaV2.1-dependent mechanisms, that likely include Ca(2+) influx at voltages sub-threshold for action potential generation.
    Frontiers in Cellular Neuroscience 02/2015; 9. DOI:10.3389/fncel.2015.00008 · 4.18 Impact Factor
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    • "It has been reported that superficial pyramidal cells and putative fast-spiking neurons in rat A1 cortex dominate in awake quiescent period, and their activity was largely suppressed during auditory stimuli-induced cortical desynchronization (Sakata and Harris, 2012). The firing of fastspiking neurons in rat somatosensory cortex, which is highly active during quiet wakefulness, is also dramatically suppressed during active whisking behavior (Gentet et al., 2010). "
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    ABSTRACT: In schizophrenia, evoked 40-Hz auditory steady-state responses (ASSRs) are impaired, which reflects the sensory deficits in this disorder, and baseline spontaneous oscillatory activity also appears to be abnormal. It has been debated whether the evoked ASSR impairments are due to the possible increase in baseline power. GABAergic interneuron-specific NMDA receptor (NMDAR) hypofunction mutant mice mimic some behavioral and pathophysiological aspects of schizophrenia. To determine the presence and extent of sensory deficits in these mutant mice, we recorded spontaneous local field potential (LFP) activity and its click-train evoked ASSRs from primary auditory cortex of awake, head-restrained mice. Baseline spontaneous LFP power in the pre-stimulus period before application of the first click trains was augmented at a wide range of frequencies. However, when repetitive ASSR stimuli were presented every 20 s, averaged spontaneous LFP power amplitudes during the inter-ASSR stimulus intervals in the mutant mice became indistinguishable from the levels of control mice. Nonetheless, the evoked 40-Hz ASSR power and their phase locking to click trains were robustly impaired in the mutants, although the evoked 20-Hz ASSRs were also somewhat diminished. These results suggested that NMDAR hypofunction in cortical GABAergic neurons confers two brain state-dependent LFP abnormalities in the auditory cortex; (1) a broadband increase in spontaneous LFP power in the absence of external inputs, and (2) a robust deficit in the evoked ASSR power and its phase-locking despite of normal baseline LFP power magnitude during the repetitive auditory stimuli. The "paradoxically" high spontaneous LFP activity of the primary auditory cortex in the absence of external stimuli may possibly contribute to the emergence of schizophrenia-related aberrant auditory perception.
    Frontiers in Neuroscience 07/2014; 8:168. DOI:10.3389/fnins.2014.00168 · 3.70 Impact Factor
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