An Acute Effect of Neuregulin 1β to Suppress α7-Containing Nicotinic Acetylcholine Receptors in Hippocampal Interneurons

Chang, Qing; Fischbach, Gerald D.

doi:10.1523/jneurosci.1794-06.2006

Cited by 37 publications

(43 citation statements)

References 48 publications

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“…Importantly, there is a lowered level of neuregulin in the synaptic complex isolated from the brain of schizophrenics [152,154]. The effects of neuregulin are not likely to be exclusively on glutamatergic transmission, as nicotinic and GABAergic transmission are also affected [155][156][157].…”

Section: Nrg1mentioning

confidence: 99%

Circuit-based framework for understanding neurotransmitter and risk gene interactions in schizophrenia

Lisman

Coyle

Green

et al. 2008

Trends in Neurosciences

913

824

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Many risk genes interact synergistically to produce schizophrenia and many neurotransmitter interactions have been implicated. We have developed a circuit-based framework for understanding gene and neurotransmitter interactions. NMDAR hypofunction has been implicated in schizophrenia because NMDAR antagonists reproduce symptoms of the disease. One action of antagonists is to reduce the excitation of fast-spiking interneurons, resulting in disinhibition of pyramidal cells. Overactive pyramidal cells, notably those in the hippocampus, can drive a hyperdopaminergic state that produces psychosis. Additional aspects of interneuron function can be understood in this framework, as follows. (i) In animal models, NMDAR antagonists reduce parvalbumin and GAD67, as found in schizophrenia. These changes produce further disinhibition and can be viewed as the aberrant response of a homeostatic system having a faulty activity sensor (the NMDAR). (ii) Disinhibition decreases the power of gamma oscillation and might thereby produce negative and cognitive symptoms. (iii) Nicotine enhances the output of interneurons, and might thereby contribute to its therapeutic effect in schizophrenia.

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Section: Nrg1mentioning

confidence: 99%

Circuit-based framework for understanding neurotransmitter and risk gene interactions in schizophrenia

Lisman

Coyle

Green

et al. 2008

Trends in Neurosciences

913

824

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“…4E, NRG2 results in phosphoactivation of PKCγ but not PKCα/βII. To selectively block PKC activation, we included an inhibitory PKC (19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30)(31)(32)(33)(34)(35)(36) peptide (10 μM) in the intracellular solution. As illustrated in Fig.…”

Section: Nrg2 Alters Gabar Currents Through Clathrin-dependent Endocymentioning

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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“…Reduction in forebrain NMDA receptors has been reported in TM-NRG1 mutants (Stefansson et al, 2002) and abnormalities in social behaviour have been reported in hypomorphic NMDA mutants (Mohn et al, 1999;Duncan et al, 2004); however, these studies did not resolve sociability vs social novelty. There is also evidence for α7 nicotinic acetylcholine receptor [α7nAChR] dysregulation in schizophrenia (Leonard and Freeman, 2006;Olincy et al, 2006), for NRG1 modulation of α7nAChR currents (Chang and Fischbach, 2006) and for the involvement of the α7nAChR in social recognition (van Kampen et al, 2004). Regarding the long-standing dopamine [DA] hyperfunction hypothesis of schizophrenia (Kapur et al, 2005;Seeman et al, 2006), NRG1 can regulate aspects of DAergic neurotransmission (Yurek et al, 2004) and DAergic dysfunction, particularly in the medial prefrontal cortex, has been implicated in the detection of salient social and non-social stimuli (O'Tuathaigh et al, 2003;Bassareo et al, 2002;De Leonibus et al, 2006).…”

Section: Nrg1 and Schizophreniamentioning

confidence: 99%

Phenotypic characterization of spatial cognition and social behavior in mice with ‘knockout’ of the schizophrenia risk gene neuregulin 1

et al. 2007

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An Acute Effect of Neuregulin 1β to Suppress α7-Containing Nicotinic Acetylcholine Receptors in Hippocampal Interneurons

Cited by 37 publications

References 48 publications

Circuit-based framework for understanding neurotransmitter and risk gene interactions in schizophrenia

Circuit-based framework for understanding neurotransmitter and risk gene interactions in schizophrenia

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

Phenotypic characterization of spatial cognition and social behavior in mice with ‘knockout’ of the schizophrenia risk gene neuregulin 1

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An Acute Effect of Neuregulin 1β to Suppress α7-Containing Nicotinic Acetylcholine Receptors in Hippocampal Interneurons

Cited by 37 publications

References 48 publications

Circuit-based framework for understanding neurotransmitter and risk gene interactions in schizophrenia

Circuit-based framework for understanding neurotransmitter and risk gene interactions in schizophrenia

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

Phenotypic characterization of spatial cognition and social behavior in mice with ‘knockout’ of the schizophrenia risk gene neuregulin 1

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