Title | Mice lacking Astn2 have ASD-like behaviors and altered cerebellar circuit properties. |
Publication Type | Journal Article |
Year of Publication | 2024 |
Authors | Hanzel M, Fernando K, Maloney SE, Horn Z, Gong S, Mätlik K, Zhao J, H Pasolli A, Heissel S, Dougherty JD, Hull C, Hatten ME |
Journal | Proc Natl Acad Sci U S A |
Volume | 121 |
Issue | 34 |
Pagination | e2405901121 |
Date Published | 2024 Aug 20 |
ISSN | 1091-6490 |
Keywords | Animals, Autism Spectrum Disorder, Behavior, Animal, Cerebellum, Disease Models, Animal, Male, Membrane Proteins, Mice, Mice, Knockout, Nerve Tissue Proteins, Purkinje Cells |
Abstract | Astrotactin 2 (ASTN2) is a transmembrane neuronal protein highly expressed in the cerebellum that functions in receptor trafficking and modulates cerebellar Purkinje cell (PC) synaptic activity. Individuals with ASTN2 mutations exhibit neurodevelopmental disorders, including autism spectrum disorder (ASD), attention-deficit/hyperactivity disorder (ADHD), learning difficulties, and language delay. To provide a genetic model for the role of the cerebellum in ASD-related behaviors and study the role of ASTN2 in cerebellar circuit function, we generated global and PC-specific conditional Astn2 knockout (KO and cKO, respectively) mouse lines. Astn2 KO mice exhibit strong ASD-related behavioral phenotypes, including a marked decrease in separation-induced pup ultrasonic vocalization calls, hyperactivity, repetitive behaviors, altered behavior in the three-chamber test, and impaired cerebellar-dependent eyeblink conditioning. Hyperactivity and repetitive behaviors are also prominent in Astn2 cKO animals, but they do not show altered behavior in the three-chamber test. By Golgi staining, Astn2 KO PCs have region-specific changes in dendritic spine density and filopodia numbers. Proteomic analysis of Astn2 KO cerebellum reveals a marked upregulation of ASTN2 family member, ASTN1, a neuron-glial adhesion protein. Immunohistochemistry and electron microscopy demonstrate a significant increase in Bergmann glia volume in the molecular layer of Astn2 KO animals. Electrophysiological experiments indicate a reduced frequency of spontaneous excitatory postsynaptic currents (EPSCs), as well as increased amplitudes of both spontaneous EPSCs and inhibitory postsynaptic currents in the Astn2 KO animals, suggesting that pre- and postsynaptic components of synaptic transmission are altered. Thus, ASTN2 regulates ASD-like behaviors and cerebellar circuit properties. |
DOI | 10.1073/pnas.2405901121 |
Alternate Journal | Proc Natl Acad Sci U S A |
PubMed ID | 39150780 |
PubMed Central ID | PMC11348334 |
Grant List | Fellowship / / Sigrid Juselius Foundation / R01 NS128054 / NS / NINDS NIH HHS / United States P50HD103525 / / HHS | NIH | Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) / 5R01NS116089 / / HHS | NIH | National Institute of Neurological Disorders and Stroke (NINDS) / R01NS128054 R01NS112917 / / HHS | NIH | National Institute of Neurological Disorders and Stroke (NINDS) / R01 NS116089 / NS / NINDS NIH HHS / United States P50 HD103525 / HD / NICHD NIH HHS / United States Fellowship / / Leon Levy Foundation / R01 NS112917 / NS / NINDS NIH HHS / United States UL1 TR000043 / TR / NCATS NIH HHS / United States |