{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,1,16]],"date-time":"2026-01-16T01:26:35Z","timestamp":1768526795317,"version":"3.49.0"},"posted":{"date-parts":[[2025,8,1]]},"group-title":"Neuroscience","reference-count":124,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2025,8,1]],"date-time":"2025-08-01T00:00:00Z","timestamp":1754006400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"name":"National Institute of Mental Helath, USA","award":["R01MH129749"],"award-info":[{"award-number":["R01MH129749"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2025,8,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  Mutations in\n                  <jats:italic>Shank3<\/jats:italic>\n                  are the primary genetic cause of Phelan-McDermid Syndrome (PMS), a neurodevelopmental disorder frequently comorbid with autism spectrum disorder (ASD). As a key scaffolding protein in the postsynaptic site, SHANK3 is critical for excitatory glutamatergic synapse function by interacting with AMPARs, NMDARs, and mGluRs. While\n                  <jats:italic>Shank3<\/jats:italic>\n                  deficiency has been extensively studied in forebrain regions, its role in the cerebellum, a brain area increasingly implicated in ASD pathobiology, remains comparatively underexplored. Cerebellar granule cells (CGCs) exhibit high\n                  <jats:italic>Shank3<\/jats:italic>\n                  expression. However, its role in cerebellar glutamatergic synapses is poorly understood. This study aims to investigate how\n                  <jats:italic>Shank3<\/jats:italic>\n                  loss affects mossy fiber-CGC glutamatergic synaptic function.\n                <\/jats:p>\n                <jats:p>\n                  Whole-cell patch clamp electrophysiological recordings from CGCs in\n                  <jats:italic>ex vivo<\/jats:italic>\n                  cerebellar brain slices from adult (4-6 months old) wild type (WT) and homozygous\n                  <jats:italic>Shank3<\/jats:italic>\n                  <jats:sup>\n                    \u0394\n                    <jats:italic>ex4-22<\/jats:italic>\n                  <\/jats:sup>\n                  KO were performed to record miniature, evoked, and glutamate uncaged responses. Similarly, the current-voltage (I-V) relationship was analyzed with intracellular spermine and pharmacological validation of calcium-permeable AMPARs (CP-AMPARs) was done by IEM-1460. Immunofluorescence staining was performed for microglia using IBA1 labeling.\n                <\/jats:p>\n                <jats:p>\n                  We found a significant increase in mEPSC amplitude and AMPAR-mediated response to glutamate uncaging, which indicates that the loss of\n                  <jats:italic>Shank3<\/jats:italic>\n                  enhances postsynaptic AMPAR function. Furthermore, the KO group showed faster AMPAR decay kinetics, inward rectification, and increased sensitivity to IEM-1460, suggesting that a high proportion of CP-AMPARs with distinct biophysical properties are present at the MF-CGC synapse. Furthermore, KO mice showed less ramified microglia suggesting the possible presence of activated microglia in the cerebellar cortex.\n                <\/jats:p>\n                <jats:p>\n                  Together, these findings highlight a critical role of\n                  <jats:italic>Shank3<\/jats:italic>\n                  in maintaining the balance between CP- and CI-AMPARs at the MF-CGC synapse, which is essential for synapse maturation and proper cerebellar circuitry function. Dysregulation of this balance, with possible presence of activated microglia in the cerebellum, may underscore cerebellar-related behavioral deficits in\n                  <jats:italic>Shank3<\/jats:italic>\n                  KO mice and may suggest a potential mechanism contributing to ASD pathophysiology.\n                <\/jats:p>","DOI":"10.1101\/2025.08.01.668222","type":"posted-content","created":{"date-parts":[[2025,8,2]],"date-time":"2025-08-02T07:45:11Z","timestamp":1754120711000},"source":"Crossref","is-referenced-by-count":0,"title":["<i>Shank3<\/i>\n                  establishes AMPA receptor subunit composition at cerebellar mossy fiber-granule cell synapses and shapes regional microglia activation"],"prefix":"10.64898","author":[{"given":"Rajaram","family":"Kshetri","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ben 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