BOD1 regulates the cerebellar IV/V lobe-fastigial nucleus circuit associated with motor coordination
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA819408 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR18463453_1.fastq.gz | Fastqsanger.gz | |||
| SRR18463453_2.fastq.gz | Fastqsanger.gz | |||
| SRR18463454_1.fastq.gz | Fastqsanger.gz | |||
| SRR18463454_2.fastq.gz | Fastqsanger.gz | |||
| SRR18463455_1.fastq.gz | Fastqsanger.gz |
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Project description:BOD1 plays an important role in modulating of the cerebellar IV/V lobePCs→FNCaMKIIα+ circuit and provide therapeutic targets for the treatment of ataxia behaviors.
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Project description:Cerebellar ataxias are characterized by a progressive decline in motor coordination, but the specific output circuits and underlying pathological mechanism remain poorly understood. Through cell-type-specific manipulations, we discovered a novel GABAergic Purkinje cell (PC) circuit in the cerebellar IV/V lobe that projected to CaMKIIα+ neurons in the fastigial nucleus (FN), which regulated sensorimotor coordination. Furthermore, transcriptomics profiling analysis revealed various cerebellar neuronal identities, and we validated that biorientation defective 1 (BOD1) played an important role in the circuit of IV/V lobe to FN. BOD1 deficit in PCs of IV/V lobe attenuated the excitability and spine density of PCs, accompany with ataxia behaviors. Instead, BOD1 enrichment in PCs of IV/V lobe reversed the hyperexcitability of CaMKIIα+ neurons in the FN and ameliorated ataxia behaviors in L7-Cre; BOD1f/f mice. Together, these findings further suggest that specific regulation of the cerebellar IV/V lobePCs → FNCaMKIIα+ circuit might provide neuromodulatory targets for the treatment of ataxia behaviors.
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Project description: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), 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 exhibited strong ASD-related behavioral phenotypes, including a marked decrease in separation-induced pup ultrasonic vocalization calls, hyperactivity, and repetitive behaviors, altered behavior in the three-chamber test, and impaired cerebellar-dependent eyeblink conditioning. Hyperactivity and repetitive behaviors were also prominent in Astn2 cKO animals but they did not show altered behavior in the three-chamber test. By Golgi staining, Astn2 KO PCs had region-specific changes in dendritic spine density and filopodia numbers. Proteomic analysis of Astn2 KO cerebellum revealed a marked upregulation of ASTN2 family member, ASTN1, a neuron-glial adhesion protein. Immunohistochemistry and electron microscopy demonstrated a significant increase in Bergmann glia volume in the molecular layer of Astn2 KO animals. Electrophysiological experiments indicated a reduced frequency of spontaneous excitatory postsynaptic currents (EPSCs), as well as increased amplitudes of both spontaneous EPSCs and inhibitory postsynaptic currents (IPSCs) in the Astn2 KO animals, suggesting that pre- and postsynaptic components of synaptic transmission were altered. Thus, ASTN2 regulates ASD-like behaviors and cerebellar circuit properties.
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Project description:Astrotactin 2 (ASTN2) is a transmembrane, neuronal protein that functions in receptor trafficking and modulates cerebellar Purkinje cell (PC) synaptic activity. We recently reported a family with a paternally inherited intragenic ASTN2 duplication, with a range of neurodevelopmental disorders, including autism spectrum disorder (ASD), learning difficulties and speech and language delay. To provide a genetic model for the role of the cerebellum in ASD-related behaviors and study ASTN2 role in cerebellar circuit function, we generated global and Purkinje cell-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 (USV) calls, increased hyperactivity and repetitive behaviors, altered social behaviors, and impaired cerebellar-dependent eyeblink conditioning. Increased hyperactivity and repetitive behaviors were also prominent in Astn2 cKO animals. 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 demonstrates a large increase in Bergmann glia volume in the molecular layer of Astn2 KO animals. Electrophysiological experiments indicate a reduced frequency of spontaneous EPSCs, as well as increased amplitudes of both spontaneous EPSCs and IPSCs in the Astn2 KO animals, suggesting that pre- and post-synaptic components of synaptic transmission are altered. Thus, ASTN2 regulates ASD-like behaviors and cerebellar circuit properties.
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Project description:Mice lacking Astn2 have ASD-like behaviors and altered cerebellar circuit properties
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