Mutation of neuron-specific chromatin remodeling subunit BAF53b: rescue of plasticity and memory by manipulating actin remodeling

Abstract

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.

Deleting HDAC3 rescues long-term memory impairments induced by disruption of the neuron-specific chromatin remodeling subunit BAF53b

“…To determine whether deletion of HDAC3 ameliorates memory impairments in BAF53b mutant mice, we generated a double mutant by crossing two mouse lines previously used by our laboratory: HDAC3 flox/flox mice and BAF53bΔSB2 mice (Vogel Ciernia et al 2017). HDAC3 flox/flox mice carry LoxP sites flanking exons four through seven in the Hdac3 gene, so that local infusion of AAV-CaMKII-Cre creates a site-specific deletion of Hdac3 in excitatory neurons .…”

“…HDAC3 flox/flox mice carry LoxP sites flanking exons four through seven in the Hdac3 gene, so that local infusion of AAV-CaMKII-Cre creates a site-specific deletion of Hdac3 in excitatory neurons . BAF53bΔSB2 mice express a transgene with a mutant form of BAF53b with a deletion of subdomain two, the region of BAF53b that is most distinct from BAF53a, its non-neuronal homolog (Vogel Ciernia et al 2017). This mutant transgene is expressed under the CaMKIIα promoter, restricting expression to forebrain excitatory neurons during post-natal development.…”

“…To verify the deletion of HDAC3 protein in HDAC3 flox/flox mice, 20 µm slices were collected throughout the dorsal hippocampus and immunofluorescence was performed and quantified as previously described Kwapis et al 2017). To verify the presence of the mutant transgene in BAF53bΔSB2 mice, punches (1.0 µm diameter) were also collected from area CA1 of the dorsal hippocampus and RT-qPCR was performed to measure expression of the BAF53bΔSB2 transgene as previously described (White et al 2016;Vogel Ciernia et al 2017).…”

“…The following day, mice were given a training trial (Fig. 1D), in which they were placed into the context with two identical objects for 10 min, a protocol that produces robust long-term memory in young wild-type mice (Vogel Ciernia et al 2017). Twenty-four hours later, mice were given a 5-min retention test in which one object was moved to a new location in a counterbalanced manner (Fig.…”

Bcl11 Transcription Factors Regulate Cortical Development and Function

“…As an example, BAF53a in pnBAF is replaced by BAF53b in nBAF complexes which coincides with the transition from mitotic to post-mitotic stages of the cell (Alfert et al, 2019). Failure of this replacement of factors results in impaired progenitor cell proliferation and dendritic morphogenesis as well as learning and memory impairment (Vogel-Ciernia et al, 2013;Vogel Ciernia et al, 2017).…”