Properties of GABA<sub>A</sub>Receptors Underlying Inhibitory Synaptic Currents in Neocortical Pyramidal Neurons

Galarreta, Mario; Hestrin, Shaul

doi:10.1523/jneurosci.17-19-07220.1997

Cited by 79 publications

(73 citation statements)

References 41 publications

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“…These results suggest that the synaptic GABA concentration transient is subsaturating for a significant proportion of the postsynaptic GABA A receptors. These observations support earlier conclusions based on the modulation of IPSCs and miniature IPSCs by benzodiazepines (Rogers et al, 1994;Frerking et al, 1995;Perrais and Ropert, 1997) and on the rapid application of subsaturating GABA concentrations (Galarreta and Hestrin, 1997). Moreover, they indicate that rapid application of saturating GABA concentrations, although very usef ul in the study of GABA A receptor kinetics, fails to duplicate important features of the synaptic GABA transient.…”

Section: Abstract: Epilepsy; Gaba; Gaba a Receptor; Hippocampus; Ipssupporting

confidence: 89%

Contribution of Subsaturating GABA Concentrations to IPSCs in Cultured Hippocampal Neurons

Hill¹,

Reddy

Covey

et al. 1998

J. Neurosci.

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The time course of EPSCs and IPSCs is at least partly determined by the concentration profile of neurotransmitter acting on postsynaptic receptors. Several recent reports have suggested that the peak synaptic cleft concentration of the inhibitory neurotransmitter GABA likely reaches at least 500 M, a level that saturates the GABA A receptor. In the course of investigating the experimental anticonvulsant 3,3-diethyl-2-pyrrolidinone (diethyl-lactam), we have observed an important contribution to IPSC decay by subsaturating concentrations of GABA. Diethyl-lactam augments currents elicited by the exogenous application of subsaturating concentrations of GABA in voltage-clamped, cultured hippocampal neurons and significantly prolongs the decay of autaptic IPSCs and miniature IPSCs in our cultures. In addition, diethyl-lactam potentiates currents in excised outside-out membrane patches elicited by the prolonged application of low concentrations of GABA. However, when patches are exposed to 1-2 msec pulses of 1 mM GABA, diethyl-lactam does not alter current decay. Tiagabine, which blocks GABA reuptake, does not prolong IPSCs, so it is unlikely that uptake inhibition accounts for the enhancement of IPSCs. EPSCs and miniature IPSC frequency are unaffected by diethyl-lactam, again consistent with a postsynaptic site of action. We propose that during an IPSC, a substantial number of postsynaptic receptors must be exposed to subsaturating concentrations of GABA. A simplified model of GABA A receptor kinetics can account for the effects of diethyllactam on exogenous GABA and IPSCs if diethyl-lactam has its main effect on the monoliganded states of the GABA A receptor. Key words: epilepsy; GABA; GABA A receptor; hippocampus; IPSC; outside-out patches; rapid application; synapseThe factors that regulate GABA A receptor-mediated inhibitory synaptic transmission are the focus of intense study because GABAergic inhibition plays a significant role in regulating electrical activity in the C NS. Furthermore, the GABA A receptor appears to be a target for anticonvulsants, sedative hypnotics, anesthetics, and anxiolytics. Benzodiazepines, barbiturates, neurosteroids, and the ␥-butyrolactones are compounds that are known to enhance GABAergic inhibition (Macdonald et al., 1989b;T w yman and Macdonald, 1992;Rogers et al., 1994;Mathews et al., 1996).The duration of the synaptic GABA transient is determined by diffusion and uptake, depending on experimental preparation and conditions Lambert, 1992, 1994;Isaacson et al., 1993;Draguhn and Heinemann, 1996). The time course of the IPSC is dictated by these factors and by the kinetics of the GABA A receptor. Several groups have studied the duration and magnitude of the synaptic GABA transient (Maconochie et al., 1994;Jones and Westbrook, 1995;Tia et al., 1996) and shown that IPSCs can be partly mimicked by exposing excised outside-out patches to high (Ն500 M) concentrations of GABA for a few milliseconds. These experiments support the idea that IPSCs result from a very brief exposure of postsyn...

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Section: Abstract: Epilepsy; Gaba; Gaba a Receptor; Hippocampus; Ipssupporting

confidence: 89%

Contribution of Subsaturating GABA Concentrations to IPSCs in Cultured Hippocampal Neurons

Hill¹,

Reddy

Covey

et al. 1998

J. Neurosci.

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“…In the control network, the IPSC decay time 2,b ϭ 2,ch ϭ 8 Ϯ 5 ms chosen with a uniform distribution and is selected to be representative of GABA A decay kinetics (Salin and Prince 1996a,b;Whittington et al 1995). There is some debate about the biophysically relevant decay times for GABA A in cortex with both fairly short (3.71 ms) and extremely long (33.2 ms) decay times reported (Galaretta and Hestrin 1997;Hefti and Smith 2002) although there is agreement that GABA A decay is generally longer than AMPA type excitatory currents. We choose 8 ms as the mean decay time both because it is an intermediate value in the range of reported values and because decay times in the 6-to 10-ms range are traditionally used in the modeling literature (Börgers et al 2005;Börgers and Kopell 2003;Cunningham et al 2004;Whittington et al 1995).…”

Section: Genesis Model Methodsmentioning

confidence: 99%

Modeling Gaba Alterations in Schizophrenia: A Link Between Impaired Inhibition and Altered Gamma and Beta Range Auditory Entrainment

Vierling-Claassen¹,

Siekmeier²,

Stufflebeam³

2008

Schizophrenia Research

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Vierling-Claassen D, Siekmeier P, Stufflebeam S, Kopell N. Modeling GABA alterations in schizophrenia: a link between impaired inhibition and altered gamma and beta range auditory entrainment. J Neurophysiol 99: 2656 -2671, 2008. First published February 20, 2008 doi:10.1152/jn.00870.2007. The disorganized symptoms of schizophrenia, including severely disordered thought patterns, may be indicative of a problem with the construction and maintenance of cell assemblies during sensory processing and attention. The gamma and beta frequency bands (15-70 Hz) are believed relevant to such processing. This paper addresses the results of an experimental examination of the cortical response of 12 schizophrenia patients and 12 control subjects when presented with auditory click-train stimuli in the gamma/beta frequency band during measurement using magnetoencephalography (MEG), as well as earlier work by Kwon et al. These data indicate that control subjects show an increased 40-Hz response to both 20-and 40-Hz stimulation as compared with patients, whereas schizophrenic subjects show a preference for 20-Hz response to the same driving frequencies. In this work, two computational models of the auditory cortex are constructed based on postmortem studies that indicate cortical interneurons in schizophrenic subjects have decreased GAT-1 (a GABA transporter) and GAD 67 (1 of 2 enzymes responsible for GABA synthesis). The models transition from control to schizophrenic frequency response when an extended inhibitory decay time is introduced; this change captures a possible effect of these GABA alterations. Modeling gamma/beta range auditory entrainment in schizophrenia provides insight into how biophysical mechanisms can impact cognitive function. In addition, the study of dynamics that underlie auditory entrainment in schizophrenia may contribute to the understanding of how gamma and beta rhythms impact cognition in general.

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“…Another benefit of mixed inhibition might derive from the different gating mechanisms of GABA A Rs and GlyRs (Dieudonné and Diana, 2009), allowing neurons to tune IPSC kinetics rapidly. GABA A Rs are assembled from a wide combination of subunits displaying very diverse affinities (Moss and Smart, 2001), and deactivation kinetics appear related to the affinity for GABA, and thus subunit composition (Jones et al, 1998(Jones et al, , 2001, and not to the concentration of GABA in the cleft (Galarreta and Hestrin, 1997;Nusser et al, 2001). The homogeneous value of the fast decay of GABAergic conductances (Fig.…”

Section: Different Dynamic Properties Of the Gaba And Glycine Componentsmentioning

confidence: 99%

Mixed Inhibitory Synaptic Balance Correlates with Glutamatergic Synaptic Phenotype in Cerebellar Unipolar Brush Cells

Rousseau¹,

Dugué²,

Dumoulin³

et al. 2012

J. Neurosci.

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Inhibitory synapses display a great diversity through varying combinations of presynaptic GABA and glycine release and postsynaptic expression of GABA and glycine receptor subtypes. We hypothesized that increased flexibility offered by this dual transmitter system might serve to tune the inhibitory phenotype to the properties of afferent excitatory synaptic inputs in individual cells. Vestibulocerebellar unipolar brush cells (UBC) receive a single glutamatergic synapse from a mossy fiber (MF), which makes them an ideal model to study excitatory-inhibitory interactions. We examined the functional phenotypes of mixed inhibitory synapses formed by Golgi interneurons onto UBCs in rat slices. We show that glycinergic IPSCs are present in all cells. An additional GABAergic component of large amplitude is only detected in a subpopulation of UBCs. This GABAergic phenotype is strictly anti-correlated with the expression of type II, but not type I, metabotropic glutamate receptors (mGluRs) at the MF synapse. Immunohistochemical stainings and agonist applications show that global UBC expression of glycine and GABA A receptors matches the pharmacological profile of IPSCs. Paired recordings of Golgi cells and UBCs confirm the postsynaptic origin of the inhibitory phenotype, including the slow kinetics of glycinergic components. These results strongly suggest the presence of a functional coregulation of excitatory and inhibitory phenotypes at the single-cell level. We propose that slow glycinergic IPSCs may provide an inhibitory tone, setting the gain of the MF to UBC relay, whereas large and fast GABAergic IPSCs may in addition control spike timing in mGluRII-negative UBCs.

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Properties of GABA_AReceptors Underlying Inhibitory Synaptic Currents in Neocortical Pyramidal Neurons

Cited by 79 publications

References 41 publications

Contribution of Subsaturating GABA Concentrations to IPSCs in Cultured Hippocampal Neurons

Contribution of Subsaturating GABA Concentrations to IPSCs in Cultured Hippocampal Neurons

Modeling Gaba Alterations in Schizophrenia: A Link Between Impaired Inhibition and Altered Gamma and Beta Range Auditory Entrainment

Mixed Inhibitory Synaptic Balance Correlates with Glutamatergic Synaptic Phenotype in Cerebellar Unipolar Brush Cells

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Properties of GABAAReceptors Underlying Inhibitory Synaptic Currents in Neocortical Pyramidal Neurons

Cited by 79 publications

References 41 publications

Contribution of Subsaturating GABA Concentrations to IPSCs in Cultured Hippocampal Neurons

Contribution of Subsaturating GABA Concentrations to IPSCs in Cultured Hippocampal Neurons

Modeling Gaba Alterations in Schizophrenia: A Link Between Impaired Inhibition and Altered Gamma and Beta Range Auditory Entrainment

Mixed Inhibitory Synaptic Balance Correlates with Glutamatergic Synaptic Phenotype in Cerebellar Unipolar Brush Cells

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Properties of GABA_AReceptors Underlying Inhibitory Synaptic Currents in Neocortical Pyramidal Neurons