Epileptogenesis and Enhanced Prepulse Inhibition in GABAB1-Deficient Mice

Prosser, Haydn M.; Gill, Catherine H.; Hirst, Warren D.; Grau, Evelyn; Robbins, Melanie J.; Calver, Andrew; Soffin, Ellen M.; Farmer, Clare; Lanneau, Christophe; Gray, Julie; Schenck, Emanuel; Warmerdam, Bastiaan S.; Clapham, Colin M.; Reavill, Charlie; Rogers, Derek C.; Stean, Tania O.; Upton, Neil; Humphreys, Kevin; Randall, Andrew D.; Geppert, Martin; Davies, Ceri H.; Pangalos, Menelas N.

doi:10.1006/mcne.2001.0995

Cited by 260 publications

(209 citation statements)

References 37 publications

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“…Our study raises the possibility that persistence of epileptic seizures in GABA B R-deficient mice (13)(14)(15) is directly linked to impairments in a homeostatic control system.…”

Section: Significancementioning

confidence: 79%

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GABA _B receptor deficiency causes failure of neuronal homeostasis in hippocampal networks

Vertkin

Styr

Slomowitz

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Stabilization of neuronal activity by homeostatic control systems is fundamental for proper functioning of neural circuits. Failure in neuronal homeostasis has been hypothesized to underlie common pathophysiological mechanisms in a variety of brain disorders. However, the key molecules regulating homeostasis in central mammalian neural circuits remain obscure. Here, we show that selective inactivation of GABA B , but not GABA A , receptors impairs firing rate homeostasis by disrupting synaptic homeostatic plasticity in hippocampal networks. Pharmacological GABA B receptor (GABA B R) blockade or genetic deletion of the GB 1a receptor subunit disrupts homeostatic regulation of synaptic vesicle release. GABA B Rs mediate adaptive presynaptic enhancement to neuronal inactivity by two principle mechanisms: First, neuronal silencing promotes syntaxin-1 switch from a closed to an open conformation to accelerate soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) complex assembly, and second, it boosts spike-evoked presynaptic calcium flux. In both cases, neuronal inactivity removes tonic block imposed by the presynaptic, GB 1a -containing receptors on syntaxin-1 opening and calcium entry to enhance probability of vesicle fusion. We identified the GB 1a intracellular domain essential for the presynaptic homeostatic response by tuning intermolecular interactions among the receptor, syntaxin-1, and the Ca V 2.2 channel. The presynaptic adaptations were accompanied by scaling of excitatory quantal amplitude via the postsynaptic, GB 1b -containing receptors. Thus, GABA B Rs sense chronic perturbations in GABA levels and transduce it to homeostatic changes in synaptic strength. Our results reveal a novel role for GABA B R as a key regulator of population firing stability and propose that disruption of homeostatic synaptic plasticity may underlie seizure's persistence in the absence of functional GABA B Rs.homeostatic plasticity | GABA B receptor | synaptic vesicle release | syntaxin-1 | FRET

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“…Our study raises the possibility that persistence of epileptic seizures in GABA B R-deficient mice (13)(14)(15) is directly linked to impairments in a homeostatic control system.…”

Section: Significancementioning

confidence: 79%

“…Mice lacking functional GABA B Rs because of GB 1 or GB 2 subunit deletion display continuous spontaneous seizure activity (13)(14)(15)(16). These findings are quite counterintuitive in light of a wide range of G protein-coupled receptors that mediate synaptic inhibition and might compensate for GABA B R loss of function.…”

Section: Resultsmentioning

confidence: 99%

GABA _B receptor deficiency causes failure of neuronal homeostasis in hippocampal networks

Vertkin

Styr

Slomowitz

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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“…Experiments were performed on intact hippocampal formation (IHF) and hippocampal slices obtained from newborn [postnatal day 1 (P1) to P24] GABA B1 receptor subunit knock-out (GABA B1 -KO) and wild-type (GABA B1 -WT) mice (Prosser et al, 2001) and BDNF-KO and BDNF-WT mice (The Jackson Laboratory). The procedure for the preparation of the intact IHFs was similar to that previously described .…”

Section: Methodsmentioning

confidence: 99%

“…To address the contribution of GABA B -Rs to the development of the hippocampal circuit, we recorded miniature GABA A and glutamatergic-receptor-mediated postsynaptic currents (mGABA APSCs and mGlu-PSCs, respectively) from hippocampal CA3 pyramidal cells from P6 to P8 GABA B1 -KO mice, which display a complete loss of GABA B receptor function (Prosser et al, 2001). The frequency of mGABA A -PSCs was significantly reduced in GABA B1 -KO (0.73 Ϯ 0.12 Hz in GABA B1 -KO, n ϭ 13) when compared with their wild-type littermates (1.61 Ϯ 0.26 Hz, n ϭ 10, p ϭ 0.03) (Fig.…”

Section: Miniature Gabaergic Synaptic Activity Is Altered In Mice Lacmentioning

confidence: 99%

GABA_BReceptor Activation Triggers BDNF Release and Promotes the Maturation of GABAergic Synapses

Fiorentino¹,

Kuczewski²,

Diabira³

et al. 2009

J. Neurosci.

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GABA, the main inhibitory neurotransmitter in the adult brain, has recently emerged as an important signal in network development. Most of the trophic functions of GABA have been attributed to depolarization of the embryonic and neonatal neurons via the activation of ionotropic GABAAreceptors. Here we demonstrate a novel mechanism by which endogenous GABA selectively regulates the development of GABAergic synapses in the developing brain. Using whole-cell patch-clamp recordings on newborn mouse hippocampi lacking functional GABABreceptors (GABAB-Rs) and time-lapse fluorescence imaging on cultured hippocampal neurons expressing GFP-tagged brain-derived neurotrophic factor (BDNF), we found that activation of metabotropic GABABreceptors (GABAB-Rs) triggers secretion of BDNF and promotes the development of perisomatic GABAergic synapses in the newborn mouse hippocampus. Because activation of GABAB-Rs occurs during the characteristic ongoing physiological network-driven synaptic activity present in the developing hippocampus, our results reveal a new mechanism by which synaptic activity can modulate the development of local GABAergic synaptic connections in the developing brain.

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“…Homozygous GABA B R1 knock-out mice lack functional presynaptic and postsynaptic GABA B receptors and exhibit generalized epilepsy (Prosser et al, 2001;Schuler et al, 2001), as would be expected for the loss of slow synaptic inhibition.…”

Section: Introductionmentioning

confidence: 91%

cAMP Response Element-Binding Protein, Activating Transcription Factor-4, and Upstream Stimulatory Factor Differentially Control Hippocampal GABA_BR1a and GABA_BR1b Subunit Gene Expression through Alternative Promoters

Steiger

Bandyopadhyay²,

Farb³

et al. 2004

J. Neurosci.

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Expression of metabotropic GABA B receptors is essential for slow inhibitory synaptic transmission in the CNS, and disruption of GABA B receptor-mediated responses has been associated with several disorders, including neuropathic pain and epilepsy. The location of GABA B receptors in neurons determines their specific role in synaptic transmission, and it is believed that sorting of subunit isoforms, GABA B R1a and GABA B R1b, to presynaptic or postsynaptic membranes helps to determine this role. GABA B R1a and GABA B R1b are thought to arise by alternative splicing of heteronuclear RNA. We now demonstrate that alternative promoters, rather than alternative splicing, produce GABA B R1a and GABA B R1b isoforms. Our data further show that subunit gene expression in hippocampal neurons is mediated by the cAMP response element-binding protein (CREB) by binding to unique cAMP response elements in the alternative promoter regions. Double-stranded oligonucleotide decoys selectively alter levels of endogenous GABA B R1a and GABA B R1b in primary hippocampal neurons, and CREB knock-out mice show changes in levels of GABA B R1a and GABA B R1b transcripts, consistent with decoy competition experiments. These results demonstrate a critical role of CREB in transcriptional mechanisms that control GABA B R1 subunit levels in vivo. In addition, the CREB-related factor activating transcription factor-4 (ATF4) has been shown to interact directly with GABA B R1 in neurons, and we show that ATF4 differentially regulates GABA B R1a and GABA B R1b promoter activity. These results, together with our finding that the depolarization-sensitive upstream stimulatory factor (USF) binds to a composite CREB/ATF4/USF regulatory element only in the absence of CREB binding, indicate that selective control of alternative GABA B R1 promoters by CREB, ATF4, and USF may dynamically regulate expression of their gene products in the nervous system.

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Epileptogenesis and Enhanced Prepulse Inhibition in GABAB1-Deficient Mice

Cited by 260 publications

References 37 publications

GABA _B receptor deficiency causes failure of neuronal homeostasis in hippocampal networks

GABA _B receptor deficiency causes failure of neuronal homeostasis in hippocampal networks

GABA_BReceptor Activation Triggers BDNF Release and Promotes the Maturation of GABAergic Synapses

cAMP Response Element-Binding Protein, Activating Transcription Factor-4, and Upstream Stimulatory Factor Differentially Control Hippocampal GABA_BR1a and GABA_BR1b Subunit Gene Expression through Alternative Promoters

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Epileptogenesis and Enhanced Prepulse Inhibition in GABAB1-Deficient Mice

Cited by 260 publications

References 37 publications

GABA B receptor deficiency causes failure of neuronal homeostasis in hippocampal networks

GABA B receptor deficiency causes failure of neuronal homeostasis in hippocampal networks

GABABReceptor Activation Triggers BDNF Release and Promotes the Maturation of GABAergic Synapses

cAMP Response Element-Binding Protein, Activating Transcription Factor-4, and Upstream Stimulatory Factor Differentially Control Hippocampal GABABR1a and GABABR1b Subunit Gene Expression through Alternative Promoters

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GABA _B receptor deficiency causes failure of neuronal homeostasis in hippocampal networks

GABA _B receptor deficiency causes failure of neuronal homeostasis in hippocampal networks

GABA_BReceptor Activation Triggers BDNF Release and Promotes the Maturation of GABAergic Synapses

cAMP Response Element-Binding Protein, Activating Transcription Factor-4, and Upstream Stimulatory Factor Differentially Control Hippocampal GABA_BR1a and GABA_BR1b Subunit Gene Expression through Alternative Promoters