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SARM1 deletion in parvalbumin neurons is associated with autism-like behaviors in mice.

ABSTRACT: Autism spectrum disorder (ASD), a group of neurodevelopmental disorder diseases, is characterized by social deficits, communication difficulties, and repetitive behaviors. Sterile alpha and TIR motif-containing 1 protein (SARM1) is known as an autism-associated protein and is enriched in brain tissue. Moreover, SARM1 knockdown mice exhibit autism-like behaviors. However, its specific mechanism in ASD pathogenesis remains unclear. Here we generated parvalbumin-positive interneurons (PVI)-specific conditional SARM1 knockout (SARM1^PV-CKO) mice. SARM1^PV-CKO male mice showed autism-like behaviors, such as mild social interaction deficits and repetitive behaviors. Moreover, we found that the expression level of parvalbumin was reduced in SARM1^PV-CKO male mice, together with upregulated apoptosis-related proteins and more cleaved-caspase-3-positive PVIs, suggesting that knocking out SARM1 may cause a reduction in the number of PVIs due to apoptosis. Furthermore, the expression of c-fos was shown to increase in SARM1^PV-CKO male mice, in combination with upregulation of excitatory postsynaptic proteins such as PSD-95 or neuroligin-1, indicating enhanced excitatory synaptic input in mutant mice. This notion was further supported by the partial rescue of autism-like behavior deficits by the administration of GABA receptor agonists in SARM1^PV-CKO male mice. In conclusion, our findings suggest that SARM1 deficiency in PVIs may be involved in the pathogenesis of ASD.

SUBMITTER: Xiang L

PROVIDER: S-EPMC9307765 | biostudies-literature | 2022 Jul

REPOSITORIES: biostudies-literature

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SARM1 deletion in parvalbumin neurons is associated with autism-like behaviors in mice.

Xiang Ludan L Wu Qian Q Sun Huankun H Miao Xuemeng X Lv Zhaoting Z Liu Huitao H Chen Lan L Gu Yanrou Y Chen Jianjun J Zhou Siyao S Jiang Huixia H Du Siyu S Zhou Yixin Y Dong Hui H Fan Yiren Y Miao Shuangda S Lu Qi Q Chang Liyun L Wang Hui H Lu Yi Y Xu Xingxing X Wang Wei W Huang Zhihui Z

Cell death & disease 20220722 7

Autism spectrum disorder (ASD), a group of neurodevelopmental disorder diseases, is characterized by social deficits, communication difficulties, and repetitive behaviors. Sterile alpha and TIR motif-containing 1 protein (SARM1) is known as an autism-associated protein and is enriched in brain tissue. Moreover, SARM1 knockdown mice exhibit autism-like behaviors. However, its specific mechanism in ASD pathogenesis remains unclear. Here we generated parvalbumin-positive interneurons (PVI)-specific ...[more]

PMID: 35869039

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Project description:Peripheral polyneuropathy is a common and dose-limiting side effect of many important chemotherapeutic agents. Most such neuropathies are characterized by early axonal degeneration, yet therapies that inhibit this axonal destruction process do not currently exist. Recently, we and others discovered that genetic deletion of SARM1 (sterile alpha and TIR motif containing protein 1) dramatically protects axons from degeneration after axotomy in mice. This finding fuels hope that inhibition of SARM1 or its downstream components can be used therapeutically in patients threatened by axonal loss. However, axon loss in most neuropathies, including chemotherapy-induced peripheral neuropathy, is the result of subacute/chronic processes that may be regulated differently than the acute, one time insult of axotomy. Here we evaluate if genetic deletion of SARM1 decreases axonal degeneration in a mouse model of neuropathy induced by the chemotherapeutic agent vincristine. In wild-type mice, 4 weeks of twice-weekly intraperitoneal injections of 1.5 mg/kg vincristine cause pronounced mechanical and heat hyperalgesia, a significant decrease in tail compound nerve action potential amplitude, loss of intraepidermal nerve fibres and significant degeneration of myelinated axons in both the distal sural nerve and nerves of the toe. Neither the proximal sural nerve nor the motor tibial nerve exhibit axon loss. These findings are consistent with the development of a distal, sensory predominant axonal polyneuropathy that mimics vincristine-induced peripheral polyneuropathy in humans. Using the same regimen of vincristine treatment in SARM1 knockout mice, the development of mechanical and heat hyperalgesia is blocked and the loss in tail compound nerve action potential amplitude is prevented. Moreover, SARM1 knockout mice do not lose unmyelinated fibres in the skin or myelinated axons in the sural nerve and toe after vincristine. Hence, genetic deletion of SARM1 blocks the development of vincristine-induced peripheral polyneuropathy in mice. Our results reveal that subacute/chronic axon loss induced by vincristine occurs via a SARM1 mediated axonal destruction pathway, and that blocking this pathway prevents the development of vincristine-induced peripheral polyneuropathy. These findings, in conjunction with previous studies with axotomy and traumatic brain injury, establish SARM1 as the central determinant of a fundamental axonal degeneration pathway that is activated by diverse insults. We suggest that targeting SARM1 or its downstream effectors may be a viable therapeutic option to prevent vincristine-induced peripheral polyneuropathy and possibly other peripheral polyneuropathies.

Project description:The basolateral amygdala (BLA) is increasingly recognized as a key regulator of depression and anxiety-like behaviors. However, the specific contribution of individual BLA neurons to these behaviors remains poorly understood. Building on our previous study, which demonstrated increased activity in glutamatergic BLA neurons in response to aversive stimuli and that enhancing inhibition in the BLA can alleviate depressive-like behaviors, we investigated the role of individual BLA GABAergic neurons (BLAGABA) in depressive and anxiety-like phenotypes. To address this question, we employed a comprehensive array of techniques, including c-fos staining, fiber photometry recording, optogenetic and chemogenetic manipulation, and behavior analysis. Our findings indicate that BLAGABA neurons show decreased activity during tail suspension and after chronic social defeat stress (CSDS) during social interaction. High-frequency activation of BLAGABA neurons attenuated depressive and anxiety-like behaviors, while low-frequency activation had no effect. Fiber photometry recordings revealed increased activity in BLA GABAergic neurons expressing somatostatin (SST), parvalbumin (PV), and cholecystokinin (CCK) during footshock aversive stimuli. Moreover, we found increased activity in PV and SST neurons and decreased activity in CCK-GABA neurons in the BLA during tail suspension stress. However, after CSDS, BLAPV neurons displayed decreased activity, while SST and CCK neurons showed no changes during the social interaction test. Behavioral analysis demonstrated that chemogenetic inhibition of PV and CCK-GABA neurons induced depressive and anxiety-like behaviors. whereas SST neuron inhibition had no effect. Conversely, chemogenetic activation of BLAPV neurons alleviated depressive behaviors, and activation of BLACCK-GABA neurons alleviated at least partly both depressive and anxiety-like behaviors. This study provides compelling evidence that BLAPV neurons play a critical role in regulating depressive-like behaviors, and that BLACCK-GABA neurons are involved, at least in part, in modulating both depressive-like and anxiety-like behaviors in mice.

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SARM1 deletion in parvalbumin neurons is associated with autism-like behaviors in mice.

Publications

SARM1 deletion in parvalbumin neurons is associated with autism-like behaviors in mice.

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