Title

Shank1 regulates excitatory synaptic transmission in mouse hippocampal parvalbumin-expressing inhibitory interneurons

Student Author(s)

Wenjie Mao; Jeffrey L. Frost; Sukhee Cho

Academic Program

Neuroscience

UMMS Affiliation

Department of Psychiatry; Brudnick Neuropsychiatric Research Institute; Freeman Lab; Schafer Lab; Graduate School of Biomedical Sciences, Neuroscience Program

Publication Date

2015-04-01

Document Type

Article

Disciplines

Molecular and Cellular Neuroscience

Abstract

The Shank genes (SHANK1, 2, 3) encode scaffold proteins highly enriched in postsynaptic densities where they regulate synaptic structure in spiny neurons. Mutations in human Shank genes are linked to autism spectrum disorder and schizophrenia. Shank1 mutant mice exhibit intriguing cognitive phenotypes reminiscent of individuals with autism spectrum disorder. However, the molecular mechanisms leading to the human pathophysiological phenotypes and mouse behaviors have not been elucidated. In this study it is shown that Shank1 protein is highly localized in parvalbumin-expressing (PV+) fast-spiking inhibitory interneurons in the hippocampus. Importantly, a lack of Shank1 in hippocampal CA1 PV+ neurons reduced excitatory synaptic inputs and inhibitory synaptic outputs to pyramidal neurons. Furthermore, it is demonstrated that hippocampal CA1 pyramidal neurons in Shank1 mutant mice exhibit a shift in the excitatory and inhibitory balance (E-I balance), a pathophysiological hallmark of autism spectrum disorder. The mutant mice also exhibit lower expression of gephyrin (a scaffold component of inhibitory synapses), supporting the dysregulation of E-I balance in the hippocampus. These results suggest that Shank1 scaffold in PV+ interneurons regulates excitatory synaptic strength and participates in the maintenance of E-I balance in excitatory neurons.

Keywords

GABAergic synapse, excitatory synapse, hippocampus, interneurons, synaptic transmission

DOI of Published Version

10.1111/ejn.12877

Source

Eur J Neurosci. 2015 Apr;41(8):1025-35. doi: 10.1111/ejn.12877. Epub 2015 Mar 25. Link to article on publisher's site

Journal/Book/Conference Title

The European journal of neuroscience

Related Resources

Link to Article in PubMed

PubMed ID

25816842

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