Mutation of neuron-specific chromatin remodeling subunit BAF53b: rescue of plasticity and memory by manipulating actin remodelingVogel Ciernia, A., Kramár, E. A., Matheos, D. P., Havekes, R., Hemstedt, T. J., Magnan, C. N., Sakata, K., Tran, A., Azzawi, S., Lopez, A., Dang, R., Wang, W., Trieu, B., Tong, J., Barrett, R. M., Post, R. J., Baldi, P., Abel, T., Lynch, G. & Wood, M. A. May-2017 In : Learning & Memory. 24, 5, p. 199-209 11 p.
Research output: Scientific - peer-review › Article
Recent human exome-sequencing studies have implicated polymorphic Brg1-associated factor (BAF) complexes (mammalian SWI/SNF chromatin remodeling complexes) in several intellectual disabilities and cognitive disorders, including autism. However, it remains unclear how mutations in BAF complexes result in impaired cognitive function. Post-mitotic neurons express a neuron-specific assembly, nBAF, characterized by the neuron-specific subunit BAF53b. Subdomain 2 of BAF53b is essential for the differentiation of neuronal precursor cells into neurons. We generated transgenic mice lacking subdomain 2 of Baf53b (BAF53b Delta SB2). Long-term synaptic potentiation (LTP) and long-term memory, both of which are associated with phosphorylation of the actin severing protein cofilin, were assessed in these animals. A phosphorylation mimic of cofilin was stereotaxically delivered into the hippocampus of BAF53b Delta SB2 mice in an effort to rescue LTP and memory. BAF53b Delta SB2 mutant mice show impairments in phosphorylation of synaptic cofilin, LTP, and memory. Both the synaptic plasticity and memory deficits are rescued by overexpression of a phosphorylation mimetic of cofilin. Baseline physiology and behavior were not affected by the mutation or the experimental treatment. This study suggests a potential link between nBAF function, actin cytoskeletal remodeling at the dendritic spine, and memory formation. This work shows that a targeted manipulation of synaptic function can rescue adult plasticity and memory deficits caused by manipulations of nBAF, and thereby provides potential novel avenues for therapeutic development for multiple intellectual disability disorders.
|Number of pages||11|
|Journal||Learning & Memory|
|State||Published - May-2017|
- LONG-TERM POTENTIATION, COFFIN-SIRIS SYNDROME, DE-NOVO MUTATIONS, SYNAPTIC PLASTICITY, DENDRITIC SPINES, MICROSCOPY IMAGES, DENTATE GYRUS, COMPLEX, EXPRESSION, COFILIN