A standardized social preference protocol for measuring social deficits in mouse models of autism

Mutations of the SHANK3 gene are found in some autism spectrum disorder (ASD) patients, and animal models harboring SHANK3 mutations exhibit a variety of ASD-like behaviors, presenting a unique opportunity to explore the underlying neuropathological mechanisms and potential pharmacological treatments. The histone deacetylase (HDAC) valproic acid (VPA) has demonstrated neuroprotective and neuroregenerative properties, suggesting possible therapeutic utility for ASD. Therefore, SHANK3-associated ASD-like symptoms present a convenient model to evaluate the potential benefits, therapeutic window, and optimal dose of VPA. We constructed a novel shank3-deficient (shank3ab–/–) zebrafish model through CRISPR/Cas9 editing and conducted comprehensive morphological and neurobehavioral evaluations, including of core ASD-like behaviors, as well as molecular analyses of synaptic proteins expression levels. Furthermore, different VPA doses and treatment durations were examined for effects on ASD-like phenotypes. Compared to wild types (WTs), shank3ab–/– zebrafish exhibited greater developmental mortality, more frequent abnormal tail bending, pervasive developmental delay, impaired social preference, repetitive swimming behaviors, and generally reduced locomotor activity. The expression levels of synaptic proteins were also dramatically reduced in shank3ab–/– zebrafish. These ASD-like behaviors were attenuated by low-dose (5 μM) VPA administered from 4 to 8 days post-fertilization (dpf), and the effects persisted to adulthood. In addition, the observed underexpression of grm5, encoding glutamate metabotropic receptor 5, was significantly improved in VPA-treated shank3ab–/– zebrafish. We report for the first time that low-dose VPA administered after neural tube closure has lasting beneficial effects on the social deficits and repetitive behavioral patterns in shank3-deficient ASD model zebrafish. These findings provide a promising strategy for ASD clinical drug development.

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Deletion of the voltage-gated calcium channel, CaV1.3, causes deficits in motor performance and associative learning

10.1101/2020.08.12.248120 ◽

2020 ◽

Author(s):

Marisol Lauffer ◽

Hsiang Wen ◽

Bryn Myers ◽

Ashley Plumb ◽

Krystal Parker ◽

...

Keyword(s):

Motor Learning ◽

Associative Learning ◽

Motor Performance ◽

Social Preference ◽

Neural Circuits ◽

Social Deficits ◽

Voltage Gated ◽

Voltage Gated Calcium Channels ◽

The Brain

AbstractL-type voltage-gated calcium channels (LVGCCs) are important regulators of neuronal activity and are widely expressed throughout the brain. One of the major LVGCC isoforms in the brain is CaV1.3. Mice lacking CaV1.3 (CaV1.3 KO) have impairments in fear conditioning and depressive-like behaviors, which have been linked to the role of CaV1.3 in hippocampal and amygdala function. Genetic variation in CaV1.3 has been linked to a variety of psychiatric disorders, including autism and schizophrenia, which are associated with motor, learning, and social deficits. Here, we explored whether CaV1.3 plays a role in these behaviors. We found that CaV1.3 KO mice have deficits in rotarod learning despite normal locomotor function. Deletion of CaV1.3 is also associated with impaired associative learning on the Erasmus Ladder. We did not observe any impairments in CaV1.3 KO mice on assays of anxiety-like, depression-like, or social preference behaviors. Our results suggest an important role for CaV1.3 in neural circuits involved in motor learning and concur with previous data showing its involvement in associative learning.

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