The neuron-specific chromatin regulatory subunit BAF53b is necessary for synaptic plasticity and memory

Abstract

Recent exome sequencing studies have implicated polymorphic Brg1-Associated Factor (BAF) complexes (mammalian SWI/SNF chromatin remodeling complexes) in several human intellectual disabilities and cognitive disorders. However, it is currently unknown how mutations in BAF complexes result in impaired cognitive function. Postmitotic neurons express a neuron-specific assembly, nBAF, characterized by the neuron-specific subunit BAF53b. Mice harboring selective genetic manipulations of BAF53b have severe defects in long-term memory and long-lasting forms of hippocampal synaptic plasticity. We rescued memory impairments in BAF53b mutant mice by reintroducing BAF53b in the adult hippocampus, which suggests a role for BAF53b beyond neuronal development. The defects in BAF53b mutant mice appeared to derive from alterations in gene expression that produce abnormal postsynaptic components, such as spine structure and function, and ultimately lead to deficits in synaptic plasticity. Our results provide new insight into the role of dominant mutations in subunits of BAF complexes in human intellectual and cognitive disorders.

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Figure 1: Characterization of BAF53bΔHD and Baf53b+/− mice.
Figure 2: BAF53bΔHD and Baf53b+/− mice have impaired long-term memory.
Figure 3: BAF53bΔHDlow and Baf53b+/− mice have impairments in long-term memory for contextual fear, but normal cued fear memory.
Figure 4: Hippocampal AAV-Baf53b rescues OLM, but not ORM, deficits in Baf53b+/− mice.
Figure 5: BAF53bΔHD and Baf53b+/− mice have disrupted LTP in hippocampal slices.
Figure 6: TBS-induced phosphorylation of Cofilin is altered in Baf53b+/− mice.
Figure 7: Differential gene expression in Baf53b+/− mice by RNA sequencing.

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Gene Expression Omnibus

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Acknowledgements

We wish to acknowledge the University of California at Irvine Institute for Genomics and Bioinformatics and Genomics High-Throughput Facility, and J. Hayes for additional computing support. We would like to thank J. Guzowski and T. Miyashita for their technical expertise and the use of the BX61 microscope and XC10 camera. This work was supported by grants from the US National Institutes of Health (MH081004 and DA025922 to M.A.W., and training grant T32-AG00096-29 to A.V.C.). G.L., E.K. and Y.J. were supported by grants from the US National Institutes of Health (P01 NS045260) and ONR (#N00014-10-1-0072). T.Z.B. was supported by US National Institutes of Health grants NS 28912 and MH73136. The work of M.Z., C.M. and P.B. was supported by grants from the National Science Foundation (IIS-0513376), the US National Institutes of Health (LM010235) and the National Library of Medicine (T15 LM07443) to P.B.

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A.V.-C., D.P.M., R.M.B. and M.A.W. designed the experiments. A.V.-C., D.P.M. and R.M.B. conducted the experiments. A.V.-C. and M.A.W. wrote the manuscript. E.K. and Y.J. conducted the electrophysiological experiments and analyzed the results. A.B. conducted and analyzed the pCofilin experiments. Y.C. and T.Z.B. designed and conducted the spine analysis. C.N.M., M.Z. and P.B. performed the RNA sequencing analysis. S.A., A.S., J.H., A.T., R.D. and R.J.P. performed the behavioral experiments. M.C. made the AAV-hrGFP virus. J.I.W. and G.R.C. provided technical assistance and assisted in manuscript preparation. P.B., T.Z.B. and G.L. assisted in experimental design, data analysis and manuscript preparation.

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Correspondence to Marcelo A Wood.

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Vogel-Ciernia, A., Matheos, D., Barrett, R. et al. The neuron-specific chromatin regulatory subunit BAF53b is necessary for synaptic plasticity and memory. Nat Neurosci 16, 552–561 (2013). https://doi.org/10.1038/nn.3359

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