title: Shank1 regulates excitatory synaptic transmission in mouse hippocampal parvalbumin-expressing inhibitory interneurons.
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.
authors: Brudnick Neuropsychiatric Research Institute and Program in Neuroscience, University of Massachusetts Medical School, 303 Belmont Street, Worcester, MA, 01604, USA.
authors: Wenjie
authors: W
authors: Mao
authors: Takuya
authors: T
authors: Watanabe
authors: Sukhee
authors: S
authors: Cho
authors: Jeffrey L
authors: JL
authors: Frost
authors: Tina
authors: T
authors: Truong
authors: Xiaohu
authors: X
authors: Zhao
authors: Kensuke
authors: K
authors: Futai
mesh_terms: D000818:Animals; D056547:CA1 Region, Hippocampal / Q000378:metabolism / Q000502:physiology*; D002352:Carrier Proteins / Q000378:metabolism; D059330:GABAergic Neurons / Q000378:metabolism / Q000502:physiology*; D007395:Interneurons / Q000378:metabolism; D008564:Membrane Potentials; D008565:Membrane Proteins / Q000378:metabolism; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D009433:Neural Inhibition; D010320:Parvalbumins / Q000378:metabolism; D057907:Post-Synaptic Density / Q000378:metabolism; D017966:Pyramidal Cells / Q000378:metabolism / Q000502:physiology*; D009435:Synaptic Transmission
chemical_list: D002352:Carrier Proteins; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D010320:Parvalbumins; C512412:SHANK1 protein, mouse; C073441:gephyrin
keywords: GABAergic synapse; excitatory synapse; hippocampus; interneurons; synaptic transmission