Vogel Ciernia Annie, Kramár Enikö A, Matheos Dina P, Havekes Robbert, Hemstedt Thekla J, Magnan Christophe N, Sakata Keith, Tran Ashley, Azzawi Soraya, Lopez Alberto, Dang Richard, Wang Weisheng, Trieu Brian, Tong Joyce, Barrett Ruth M, Post Rebecca J, Baldi Pierre, Abel Ted, Lynch Gary, Wood Marcelo A
Department of Medical Microbiology and Immunology, University of California, Davis, California 95656, USA.
Department of Neurobiology and Behavior, University of California, Irvine, California 92697, USA.
Learn Mem. 2017 Apr 17;24(5):199-209. doi: 10.1101/lm.044602.116. Print 2017 May.
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 (BAF53bΔSB2). 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 BAF53bΔSB2 mice in an effort to rescue LTP and memory. BAF53bΔSB2 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.
近期的人类外显子组测序研究表明，多态性的Brg1相关因子（BAF）复合物（哺乳动物的SWI/SNF染色质重塑复合物）与包括自闭症在内的多种智力残疾和认知障碍有关。然而，BAF复合物中的突变如何导致认知功能受损仍不清楚。有丝分裂后神经元表达一种神经元特异性组装体，即nBAF，其特征是含有神经元特异性亚基BAF53b。BAF53b的亚结构域2对于神经元前体细胞分化为神经元至关重要。我们构建了缺乏Baf53b亚结构域2（BAF53bΔSB2）的转基因小鼠。在这些动物中评估了与肌动蛋白切断蛋白丝切蛋白磷酸化相关的长期突触增强（LTP）和长期记忆。为了挽救LTP和记忆，将丝切蛋白的磷酸化模拟物立体定向注射到BAF53bΔSB2小鼠的海马体中。BAF53bΔSB2突变小鼠在突触丝切蛋白磷酸化、LTP和记忆方面存在缺陷。丝切蛋白磷酸化模拟物的过表达挽救了突触可塑性和记忆缺陷。基线生理和行为不受突变或实验处理的影响。这项研究表明nBAF功能、树突棘处的肌动蛋白细胞骨架重塑和记忆形成之间存在潜在联系。这项工作表明，对突触功能的靶向操纵可以挽救由nBAF操纵引起的成年可塑性和记忆缺陷，从而为多种智力残疾疾病的治疗开发提供潜在的新途径。
