Neuregulin 1 represses limbic epileptogenesis through ErbB4 in parvalbumin-expressing interneurons

Tan, Guo He; Liu, Yuan Yuan; Hu, Xiao; Yin, Dong Min; Mei, Lin; Xiong, Zichang

doi:10.1038/nn.3005

Cited by 109 publications

(86 citation statements)

References 46 publications

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“…To determine if ErbB4 is involved in glutamatergic hypofunction in ctoNrg1 mice, we determined if the deficits could be attenuated by ErbB4 heterozygous mutation, to avoid compounding effect of null mutation on the assembly and function of GABAergic circuitry (Fazzari et al, 2010; Li et al, 2012; Tan et al, 2012). Heterozygous mutation does not alter the number of GABAergic interneurons in cortex and hippocampus (Flames et al, 2004) and did not alter fEPSP slopes, mEPSC frequency and amplitude, and PPF of fEPSPs in control mice (Figures 4B-4D), in agreement with previous studies (Fazzari et al, 2010; Huang et al, 2000; Pitcher et al, 2011).…”

Section: Resultsmentioning

confidence: 99%

Reversal of Behavioral Deficits and Synaptic Dysfunction in Mice Overexpressing Neuregulin 1

Yin

Chen

et al. 2013

Neuron

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117

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Summary Neuregulin 1 (Nrg1) is a susceptibility gene of schizophrenia, a disabling mental illness that affects 1% of the general population. Here we show that ctoNrg1 mice, which mimic high levels of NRG1 observed in forebrain regions of schizophrenic patients, exhibit behavioral deficits and hypofunction of glutamatergic and GABAergic pathways. Intriguingly, these deficits were diminished when NRG1 expression returned to normal in adult mice that had been symptomatic, suggesting that damage which occurred during development is recoverable. Conversely, increase of NRG1 in adulthood was sufficient to cause glutamatergic impairment and behavioral deficits. We found that the glutamatergic impairment by NRG1 overexpression required LIM domain kinase 1 (LIMK1), which was activated in mutant mice, identifying a novel pathological mechanism. These observations demonstrate that synaptic dysfunction and behavioral deficits require continuous NRG1 abnormality in adulthood, suggesting that relevant schizophrenia may benefit from therapeutic intervention to restore NRG1 signaling.

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Section: Resultsmentioning

confidence: 99%

Reversal of Behavioral Deficits and Synaptic Dysfunction in Mice Overexpressing Neuregulin 1

Yin

Chen

et al. 2013

Neuron

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117

110

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“…12 Of note, there seems to be an association between epilepsy and schizophrenia. 9,14-16 It has been largely accepted that the C allele of rs35753505 is the risk allele that is associated with schizophrenia.…”

Section: Discussionmentioning

confidence: 99%

Contribution of NRG1 Gene Polymorphisms in Temporal Lobe Epilepsy

Zhu

Jiang

et al. 2015

J Child Neurol

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The purpose of the present study was to investigate the possible association between temporal lobe epilepsy and NRG1 gene polymorphisms. A total of 73 patients and 69 controls were involved in this study. Genomic DNAs from the patients and controls were genotyped by polymerase chain reaction-ligase detection reaction method. There was an association of rs35753505 (T>C) with temporal lobe epilepsy (χ(2) = 6.730, P = .035). The frequency of risk allele C of rs35753505 was significantly higher (69.9%) in patients compared to controls (55.8%) (χ(2) = 6.023, P = .014). Interestingly, the significant difference of NRG1 genotype and allele frequency only existed among males, but not females. In addition, no statistically significant association was found between rs6994992, rs62510682 polymorphisms, and temporal lobe epilepsy. These data indicate that rs35753505 of NRG1 plays an important role in conferring susceptibility to the temporal lobe epilepsy in a Chinese Han population.

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“…PKC | schizophrenia | hippocampus | parvalbumin | mIPSCs E rbB4 signaling regulates neuronal excitability (1,2) and synaptic plasticity (3,4) in the adult brain, and has been implicated in psychiatric disorders (5,6) and epilepsy (2,7). In the neocortex and hippocampus of rodents, monkeys, and humans, ErbB4 expression is restricted to GABAergic interneurons, and its expression is particularly high in parvalbumin-positive fastspiking (PV+) interneurons (8,9).…”

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confidence: 99%

ErbB4 reduces synaptic GABA _A currents independent of its receptor tyrosine kinase activity

Mitchell

Janssen

Karavanova

et al. 2013

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

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ErbB4 signaling in the central nervous system is implicated in neuropsychiatric disorders and epilepsy. In cortical tissue, ErbB4 associates with excitatory synapses located on inhibitory interneurons. However, biochemical and histological data described herein demonstrate that the vast majority of ErbB4 is extrasynaptic and detergent-soluble. To explore the function of this receptor population, we used unbiased proteomics, in combination with electrophysiological, biochemical, and cell biological techniques, to identify a clinically relevant ErbB4-interacting protein, the GABA A receptor α1 subunit (GABAR α1). We show that ErbB4 and GABAR α1 are robustly coexpressed in hippocampal interneurons, and that ErbB4-null mice have diminished cortical GABAR α1 expression. Moreover, we characterize a Neuregulin-mediated ErbB4 signaling modality, independent of receptor tyrosine kinase activity, that couples ErbB4 to decreased postsynaptic GABAR currents on inhibitory interneurons. Consistent with an evolving understanding of GABAR trafficking, this pathway requires both clathrin-mediated endocytosis and protein kinase C to reduce GABAR inhibitory currents, surface GABAR α1 expression, and colocalization with the inhibitory postsynaptic protein gephyrin. Our results reveal a function of ErbB4, independent of its tyrosine kinase activity, that modulates postsynaptic inhibitory control of hippocampal interneurons and may provide a novel pharmacological target in the treatment of neuropsychiatric disorders and epilepsy.PKC | schizophrenia | hippocampus | parvalbumin | mIPSCs E rbB4 signaling regulates neuronal excitability (1, 2) and synaptic plasticity (3, 4) in the adult brain, and has been implicated in psychiatric disorders (5, 6) and epilepsy (2, 7). In the neocortex and hippocampus of rodents, monkeys, and humans, ErbB4 expression is restricted to GABAergic interneurons, and its expression is particularly high in parvalbumin-positive fastspiking (PV+) interneurons (8, 9). Of note, targeted ablation of ErbB4 specifically in PV+ interneurons recapitulates behavioral abnormalities of full ErbB4-null mice, highlighting the importance of ErbB4 signaling in this GABAergic interneuron subclass (10). Moreover, gamma oscillations, a type of high-frequency network activity that depends on synchronization of local circuits by PV+ interneurons, are augmented by Neuregulin (NRG)1 in vitro in an ErbB4-dependent manner (11).In the hippocampus, the GABA A receptor α1 subunit (GABAR α1), which imparts rapid decay kinetics (12), is also selectively expressed in subsets of inhibitory interneurons, especially in PV+ neurons (13,14). Furthermore, a mutation in GABRA1 has been linked to absence seizures (15), and heterozygous Gabra1-null mice show cortical absence epileptiform activity (16). Additionally, genome-wide linkage analyses have repeatedly identified a cluster of GABAR subunits, which includes GABRA1, as a schizophrenia (SCZ) susceptibility locus (17). Therefore, identifying mechanisms that acutely regulate α1-containing GABARs o...

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Neuregulin 1 represses limbic epileptogenesis through ErbB4 in parvalbumin-expressing interneurons

Cited by 109 publications

References 46 publications

Reversal of Behavioral Deficits and Synaptic Dysfunction in Mice Overexpressing Neuregulin 1

Reversal of Behavioral Deficits and Synaptic Dysfunction in Mice Overexpressing Neuregulin 1

Contribution of NRG1 Gene Polymorphisms in Temporal Lobe Epilepsy

ErbB4 reduces synaptic GABA _A currents independent of its receptor tyrosine kinase activity

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Neuregulin 1 represses limbic epileptogenesis through ErbB4 in parvalbumin-expressing interneurons

Cited by 109 publications

References 46 publications

Reversal of Behavioral Deficits and Synaptic Dysfunction in Mice Overexpressing Neuregulin 1

Reversal of Behavioral Deficits and Synaptic Dysfunction in Mice Overexpressing Neuregulin 1

Contribution of NRG1 Gene Polymorphisms in Temporal Lobe Epilepsy

ErbB4 reduces synaptic GABA A currents independent of its receptor tyrosine kinase activity

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ErbB4 reduces synaptic GABA _A currents independent of its receptor tyrosine kinase activity