Aberrant mPFC GABAergic synaptic transmission and fear behavior in neuroligin-2 R215H knock-in mice

Jian Chen, Binbin Dong, Xiaoyi Feng, Dongyun Jiang, Gong Chen, Cheng Long, Li Yang

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Abstract

Aberrant medial prefrontal cortex (mPFC) activity is associated with neuropsychiatric disorders such as schizophrenia, but the precise role of mPFC GABAergic neurotransmission in the pathogenesis of schizophrenia remains not well understood. Neuroligin-2 (Nlgn 2) is a postsynaptic cell-adhesion protein playing an important role in inhibitory synapse formation and function. Mutations of Nlgn 2 have been reported to be associated with schizophrenia. Using a Nlgn 2 Arg215 → His215 mutation knock-in (NL2 R215H KI) mouse model of schizophrenia, we show here that inhibitory synaptic transmission, such as miniature and evoked inhibitory postsynaptic currents (mIPSCs, eIPSCs), is significantly reduced in the mPFC of NL2 R215H KI mice. The levels of inhibition-related proteins, including parvalbumin (PV), the γ2 subunit of the GABAA receptor, and a vesicular GABA transporter vGAT, are also reduced significantly in NL2 R215H KI mPFC. The reduction of GABAergic inhibition disrupts the excitation/inhibition (E/I) ratio in mPFC, and results in the subsequent abnormal gamma oscillation in the mPFC of NL2 R215H KI mice. Behavioral evaluation suggests that GABAergic deficits contribute, at least in part, to alterations in fear response, which requires balanced E/I ratio of mPFC neurons. These results suggest a pivotal role of Nlgn 2 in maintaining E/I balance in the mPFC and in the maintenance of normal behaviors governed by the mPFC.

Original languageEnglish (US)
Article number146671
JournalBrain research
Volume1730
DOIs
StatePublished - Mar 1 2020

All Science Journal Classification (ASJC) codes

  • Neuroscience(all)
  • Molecular Biology
  • Clinical Neurology
  • Developmental Biology

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