Shank1 regulates excitatory synaptic transmission in mouse hippocampal parvalbumin-expressing inhibitory interneurons
Department of Psychiatry; Brudnick Neuropsychiatric Research Institute; Freeman Lab; Schafer Lab; Graduate School of Biomedical Sciences, Neuroscience Program
Molecular and Cellular Neuroscience
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.
GABAergic synapse, excitatory synapse, hippocampus, interneurons, synaptic transmission
DOI of Published Version
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
The European journal of neuroscience
Mao, Wenjie; Watanabe, Takuya; Cho, Sukhee; Frost, Jeffrey L.; Truong, Tina; Zhao, Xiaohu; and Futai, Kensuke, "Shank1 regulates excitatory synaptic transmission in mouse hippocampal parvalbumin-expressing inhibitory interneurons" (2015). GSBS Student Publications. 1985.