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Despite evidence of regression or worsening of ASD-like symptoms in individuals with PMS, the underlying mechanisms remain unclear. Although Shank3 is highly expressed in the cerebellar cortical granule cells, its role in cerebellar function and contribution to behavioral deficits in ASD models are unknown. This study investigates behavioral changes and cerebellar synaptic alterations in\n                      <jats:italic>Shank3<\/jats:italic>\n                      <jats:sup>\n                        <jats:italic>\u0394ex4\u201322<\/jats:italic>\n                      <\/jats:sup>\n                      mice at two developmental stages.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      <jats:italic>Shank3<\/jats:italic>\n                      <jats:sup>\n                        <jats:italic>\u0394ex4\u201322<\/jats:italic>\n                      <\/jats:sup>\n                      wildtype, heterozygous, and homozygous knockout mice lacking exons 4\u201322 (all functional isoforms) were subjected to a behavioral battery in both juvenile (5\u20137 weeks old) and adult (3\u20135 months old) mouse cohorts of both sexes. Immunostaining was used to show the expression of Shank3 in the cerebellar cortex. Spontaneous excitatory postsynaptic currents (sEPSCs) from cerebellar granule cells (CGCs) were recorded by whole-cell patch-clamp electrophysiology.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Deletion of\n                      <jats:italic>Shank3<\/jats:italic>\n                      caused deficits in motor function, heightened anxiety, and repetitive behaviors. These genotype-dependent behavioral alterations were more prominent in adult mice than in juveniles. Reduced social preference was only identified in adult\n                      <jats:italic>Shank3<\/jats:italic>\n                      <jats:sup>\n                        <jats:italic>\u0394ex4\u201322<\/jats:italic>\n                      <\/jats:sup>\n                      knockout male mice, while self-grooming was uniquely elevated in males across both age groups. Heterozygous mice showed little to no changes in behavioral phenotypes in most behavioral tests. Immunofluorescence staining indicated the presence of Shank3 predominantly in the dendrite-containing rosette-like structures in CGCs, colocalizing with presynaptic markers of glutamatergic mossy fiber. Electrophysiological findings identified a parallel relationship between the age-related exacerbation of behavioral impairments and the enhancement of sEPSC amplitude in CGCs.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Limitations<\/jats:title>\n                    <jats:p>Other behavioral tests of muscle strength (grip strength test), memory (Barnes\/water maze), and communication (ultrasonic vocalization), were not performed. Further study is necessary to elucidate how Shank3 modulates synaptic function at the mossy fiber-granule cell synapse in the cerebellum and whether these changes shape the behavioral phenotype.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>\n                      Our findings reveal an age-related exacerbation of behavioral impairments in\n                      <jats:italic>Shank3<\/jats:italic>\n                      <jats:sup>\n                        <jats:italic>\u0394ex4\u201322<\/jats:italic>\n                      <\/jats:sup>\n                      mutant mice. These results suggest that Shank3 may alter the function of glutamatergic receptors at the mossy fiber-cerebellar granule cell synapse as a potential mechanism causing cerebellar disruption in ASD.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1186\/s13229-024-00628-y","type":"journal-article","created":{"date-parts":[[2024,12,4]],"date-time":"2024-12-04T06:01:21Z","timestamp":1733292081000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Behavioral decline in Shank3\u0394ex4\u201322 mice during early adulthood parallels cerebellar granule cell glutamatergic synaptic changes"],"prefix":"10.1186","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7866-745X","authenticated-orcid":false,"given":"Rajaram","family":"Kshetri","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James O.","family":"Beavers","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0668-5026","authenticated-orcid":false,"given":"Romana","family":"Hyde","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roseline","family":"Ewa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amber","family":"Schwertman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarahi","family":"Porcayo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0403-4956","authenticated-orcid":false,"given":"Ben D.","family":"Richardson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,12,4]]},"reference":[{"key":"628_CR1","doi-asserted-by":"publisher","first-page":"1","DOI":"10.15585\/mmwr.ss6904a1","volume":"69","author":"MJ Maenner","year":"2020","unstructured":"Maenner MJ, Shaw KA, Baio J, Washington A, Patrick M, DiRienzo M, et al. 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