Mice lacking<i>Astn2</i>have ASD-like behaviors and altered cerebellar circuit properties

Hanzel, Michalina; Fernando, Kayla; Maloney, Susan E; Gong, Shioaching; Mätlik, Kärt; Zhao, Jiajia; Pasolli, H Amalia; Heissel, Søren; Dougherty, Joseph D; Hull, Court; Hatten, Mary E

doi:10.1101/2024.02.18.580354

Cited by 2 publications

References 69 publications

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Mice lacking Astn2 have ASD-like behaviors and altered cerebellar circuit properties

Hanzel,

Fernando,

Maloney

et al. 2024

Proc. Natl. Acad. Sci. U.S.A.

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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.

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Mice lacking Astn2 have ASD-like behaviors and altered cerebellar circuit properties

Hanzel,

Fernando,

Maloney

et al. 2024

Proc. Natl. Acad. Sci. U.S.A.

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Novel environment exposure drives temporally defined and region-specific chromatin accessibility and gene expression changes in the hippocampus

Duffy,

Traunmüller,

Liu

et al. 2024

Preprint

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Curiosity-driven interactions with novel cues in our environment represent a common behavioral trait across the animal kingdom. Exposure to a novel environment (NE) reshapes the brain by promoting structural and functional changes in multiple brain areas, including the hippocampus. This experience-dependent circuit reorganization is thought to be driven in part by changes in gene expression. While NE exposure has been shown to rapidly induce the expression of FOS and other immediate-early gene transcription factors (IEG TFs), the downstream IEG-driven genes (e.g. late response genes) that serve to mediate NE-dependent circuit remodeling, as well as the DNA regulatory elements that drive the expression of these genes, remain largely unexplored. We employed a combination of hippocampal single-nucleus multiomics and bulk RNA sequencing of the DG, CA3, and CA1 regions to characterize over time the NE-driven gene expression and chromatin accessibility changes downstream of IEG induction. We observe strong hippocampal region-specificity in excitatory neuron late-response gene programs as well as diversity in the inhibitory neuron and non-neuronal gene responses. In addition, compared to a short exposure, prolonged exposure to NE caused more robust induction of late-response genes, suggesting that sustained environmental stimulation is more effective at triggering the long-lasting molecular changes that support memory formation. Notably, chromatin-level analyses revealed thousands of cell-type-specific changes in chromatin accessibility in response to NE exposure. Coordinated analysis of both chromatin accessibility and gene expression within individual cells revealed the Fos binding site referred to as the AP-1 motif as a major predictor of neuronal cell-type-specific late-response gene expression. Together, these data provide a rich resource of hippocampal chromatin accessibility and gene expression changes in response to novel experience, a physiological stimulus that affects learning and memory.

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Mice lackingAstn2have ASD-like behaviors and altered cerebellar circuit properties

Cited by 2 publications

References 69 publications

Mice lacking Astn2 have ASD-like behaviors and altered cerebellar circuit properties

Mice lacking Astn2 have ASD-like behaviors and altered cerebellar circuit properties

Novel environment exposure drives temporally defined and region-specific chromatin accessibility and gene expression changes in the hippocampus

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