Haploinsufficiency of Syngap1 in Striatal Indirect Pathway Neurons Alters Motor and Goal-Directed Behaviors in Mice.

Autor:	Haetzel LM; Helen Wills Neuroscience Institute, University of California, Berkeley, California 94720.; Departments of Molecular and Cell Biology, University of California, Berkeley, California 94720., Iafrati J; Departments of Molecular and Cell Biology, University of California, Berkeley, California 94720., Cording KR; Helen Wills Neuroscience Institute, University of California, Berkeley, California 94720.; Departments of Molecular and Cell Biology, University of California, Berkeley, California 94720.; Neuroscience, University of California, Berkeley, California 94720., Farhan M; Departments of Molecular and Cell Biology, University of California, Berkeley, California 94720., Noveir SD; Departments of Molecular and Cell Biology, University of California, Berkeley, California 94720., Rumbaugh G; Departments of Neuroscience and Molecular Medicine, The Herbert Wertheim UF Scripps Institute for Biomedical Innovation & Technology, Jupiter, Florida 33458.; Skaggs Graduate School of Chemical and Biological Sciences, Jupiter, Florida 33458., Bateup HS; Helen Wills Neuroscience Institute, University of California, Berkeley, California 94720 bateup@berkeley.edu.; Departments of Molecular and Cell Biology, University of California, Berkeley, California 94720.; Neuroscience, University of California, Berkeley, California 94720.; Weill Neurohub Investigator, University of California, Berkeley, California 94720.
Jazyk:	angličtina
Zdroj:	The Journal of neuroscience : the official journal of the Society for Neuroscience [J Neurosci] 2024 Nov 27; Vol. 44 (48). Date of Electronic Publication: 2024 Nov 27.
DOI:	10.1523/JNEUROSCI.1264-23.2024
Abstrakt:	SYNGAP1 is a high-confidence autism spectrum disorder (ASD) risk gene, and mutations in SYNGAP1 lead to a neurodevelopmental disorder (NDD) that presents with epilepsy, ASD, motor developmental delay, and intellectual disability. SYNGAP1 codes for Ras/Rap GTP-ase activating protein SynGAP (SynGAP). SynGAP is located in the postsynaptic density of glutamatergic synapses and regulates glutamate receptor trafficking in an activity-dependent manner. In addition to forebrain glutamatergic neurons, Syngap1 is highly expressed in the striatum, although the functions of SynGAP in the striatum have not been extensively studied. Here we show that Syngap1 is expressed in both direct and indirect pathway striatal projection neurons (dSPNs and iSPNs) in mice of both sexes. In a mouse model of Syngap1 haploinsufficiency, dendritic spine density, morphology, and intrinsic excitability are altered primarily in iSPNs, but not dSPNs. At the behavioral level, SynGAP reduction alters striatal-dependent motor learning and goal-directed behavior. Several behavioral phenotypes are reproduced by iSPN-specific Syngap1 reduction and, in turn, prevented by iSPN-specific Syngap1 rescue. These results establish the importance of SynGAP to striatal neuron function and pinpoint the indirect pathway as a key circuit in the neurobiology of SYNGAP1 -related NDD. Competing Interests: The authors declare no competing financial interests. (Copyright © 2024 Haetzel et al.)
Databáze:	MEDLINE
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