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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Gene Expression Omnibus
Day, J.J. & Sweatt, J.D. Cognitive neuroepigenetics: a role for epigenetic mechanisms in learning and memory. Neurobiol. Learn. Mem. 96, 2–12 (2011).
Zahir, F.R. & Brown, C.J. Epigenetic impacts on neurodevelopment: pathophysiological mechanisms and genetic modes of action. Pediatr. Res. 69, 92R–100R (2011).
Hargreaves, D.C. & Crabtree, G.R. ATP-dependent chromatin remodeling: genetics, genomics and mechanisms. Cell Res. 21, 396–420 (2011).
Wu, J.I., Lessard, J. & Crabtree, G.R. Understanding the words of chromatin regulation. Cell 136, 200–206 (2009).
Wang, W. et al. Purification and biochemical heterogeneity of the mammalian SWI-SNF complex. EMBO J. 15, 5370–5382 (1996).
Olave, I., Wang, W., Xue, Y., Kuo, A. & Crabtree, G.R. Identification of a polymorphic, neuron-specific chromatin remodeling complex. Genes Dev. 16, 2509–2517 (2002).
Zhao, K. et al. Rapid and phosphoinositol-dependent binding of the SWI/SNF-like BAF complex to chromatin after T lymphocyte receptor signaling. Cell 95, 625–636 (1998).
Wu, J.I. et al. Regulation of dendritic development by neuron-specific chromatin remodeling complexes. Neuron 56, 94–108 (2007).
Lessard, J. et al. An essential switch in subunit composition of a chromatin remodeling complex during neural development. Neuron 55, 201–215 (2007).
Yoo, A.S., Staahl, B.T., Chen, L. & Crabtree, G.R. MicroRNA-mediated switching of chromatin-remodeling complexes in neural development. Nature 460, 642–646 (2009).
Yoo, A.S. et al. MicroRNA-mediated conversion of human fibroblasts to neurons. Nature 476, 228–231 (2011).
Tsurusaki, Y. et al. Mutations affecting components of the SWI/SNF complex cause Coffin-Siris syndrome. Nat. Genet. 44, 376–378 (2012).
Santen, G.W.E. et al. Mutations in SWI/SNF chromatin remodeling complex gene ARID1B cause Coffin-Siris syndrome. Nat. Genet. 44, 379–380 (2012).
Van Houdt, J.K. et al. Heterozygous missense mutations in SMARCA2 cause Nicolaides-Baraitser syndrome. Nat. Genet. 44, 445–449 (2012).
Halgren, C. et al. Corpus callosum abnormalities, intellectual disability, speech impairment, and autism in patients with haploinsufficiency of ARID1B. Clin. Genet. 82, 248–255 (2012).
Hoyer, J., Ekici, A.B., Endele, S., Popp, B. & Zweier, C. Haploinsufficiency of ARID1B, a member of the SWI/SNF-A chromatin-remodeling complex, is a frequent cause of intellectual disability. Am. J. Hum. Genet. 90, 565–572 (2012).
Neale, B.M. et al. Patterns and rates of exonic de novo mutations in autism spectrum disorders. Nature 485, 242–245 (2012).
Park, J., Wood, M.A. & Cole, M.D. BAF53 forms distinct nuclear complexes and functions as a critical c-Myc–interacting nuclear cofactor for oncogenic transformation. Mol. Cell Biol. 22, 1307–1316 (2002).
Mayford, M. et al. Control of memory formation through regulated expression of a CaMKII transgene. Science 274, 1678–1683 (1996).
Kojima, N. et al. Rescuing impairment of long-term potentiation in fyn-deficient mice by introducing Fyn transgene. Proc. Natl. Acad. Sci. USA 94, 4761–4765 (1997).
Larson, J., Wong, D. & Lynch, G. Patterned stimulation at the theta frequency is optimal for the induction of hippocampal long-term potentiation. Brain Res. 368, 347–350 (1986).
Lauterborn, J.C. et al. Brain-derived neurotrophic factor rescues synaptic plasticity in a mouse model of fragile X syndrome. J. Neurosci. 27, 10685–10694 (2007).
Rex, C.S. et al. Different Rho GTPase–dependent signaling pathways initiate sequential steps in the consolidation of long-term potentiation. J. Cell Biol. 186, 85–97 (2009).
Chen, L.Y., Rex, C.S., Casale, M.S., Gall, C.M. & Lynch, G. Changes in synaptic morphology accompany actin signaling during LTP. J. Neurosci. 27, 5363–5372 (2007).
Bourne, J.N. & Harris, K.M. Balancing structure and function at hippocampal dendritic spines. Annu. Rev. Neurosci. 31, 47–67 (2008).
Grutzendler, J., Kasthuri, N. & Gan, W.B. Long-term dendritic spine stability in the adult cortex. Nature 420, 812–816 (2002).
Harris, K.M., Jensen, F.E. & Tsao, B. Three-dimensional structure of dendritic spines and synapses in rat hippocampus (CA1) at postnatal day 15 and adult ages: implications for the maturation of synaptic physiology and long-term potentiation. J. Neurosci. 12, 2685–2705 (1992).
Barrett, R.M. et al. Hippocampal focal knockout of CBP affects specific histone modifications, long-term potentiation and long-term memory. Neuropsychopharmacology 36, 1545–1556 (2011).
Fujita, P.A. et al. The UCSC Genome Browser database: update 2011. Nucleic Acids Res. 39, D876–D882 (2011).
Langmead, B., Trapnell, C., Pop, M. & Salzberg, S.L. Ultrafast and memory-efficient alignment of short DNA sequences to the human genome. Genome Biol. 10, R25 (2009).
Mortazavi, A., Williams, B.A., McCue, K., Schaeffer, L. & Wold, B. Mapping and quantifying mammalian transcriptomes by RNA-Seq. Nat. Methods 5, 621–628 (2008).
Kayala, M.A. & Baldi, P. Cyber-T web server: differential analysis of high-throughput data. Nucleic Acids Res. 40, W553–559 (2012).
Baldi, P. & Long, A.D. A Bayesian framework for the analysis of microarray expression data: regularized t -test and statistical inferences of gene changes. Bioinformatics 17, 509–519 (2001).
Alberini, C.M. Transcription factors in long-term memory and synaptic plasticity. Physiol. Rev. 89, 121–145 (2009).
Ashburner, M. et al. Gene ontology: tool for the unification of biology. The Gene Ontology Consortium. Nat. Genet. 25, 25–29 (2000).
Ogata, H. et al. KEGG: Kyoto Encyclopedia of Genes and Genomes. Nucleic Acids Res. 27, 29–34 (1999).
Kanehisa, M., Goto, S., Sato, Y., Furumichi, M. & Tanabe, M. KEGG for integration and interpretation of large-scale molecular data sets. Nucleic Acids Res. 40, D109–D114 (2012).
Dennis, G. et al. DAVID: Database for Annotation, Visualization and Integrated Discovery. Genome Biol. 4, 3 (2003).
Wayman, G.A. et al. An activity-regulated microRNA controls dendritic plasticity by down-regulating p250GAP. Proc. Natl. Acad. Sci. USA 105, 9093–9098 (2008).
Impey, S. et al. An activity-induced microRNA controls dendritic spine formation by regulating Rac1-PAK signaling. Mol. Cell Neurosci. 43, 146–156 (2010).
Hansen, K.F., Sakamoto, K., Wayman, G.A., Impey, S. & Obrietan, K. Transgenic miR132 alters neuronal spine density and impairs novel object recognition memory. PLoS ONE 5, e15497 (2010).
Fedulov, V. et al. Evidence that long-term potentiation occurs within individual hippocampal synapses during learning. J. Neurosci. 27, 8031–8039 (2007).
Fukazawa, Y. et al. Hippocampal LTP is accompanied by enhanced F-actin content within the dendritic spine that is essential for late LTP maintenance in vivo. Neuron 38, 447–460 (2003).
Klein, M.E. et al. Homeostatic regulation of MeCP2 expression by a CREB-induced microRNA. Nat. Neurosci. 10, 1513–1514 (2007).
Nelson, E.D. & Monteggia, L.M. Epigenetics in the mature mammalian brain: effects on behavior and synaptic transmission. Neurobiol. Learn. Mem. 96, 53–60 (2011).
Amir, R.E. et al. Rett syndrome is caused by mutations in X-linked MECP2, encoding methylCpG-binding protein 2. Nat. Genet. 23, 185–188 (1999).
Levenga, J. & Willemsen, R. Perturbation of dendritic protrusions in intellectual disability. Prog. Brain Res. 197, 153–168 (2012).
Aizawa, H. Dendrite development regulated by CREST, a calcium-regulated transcriptional activator. Science 303, 197–202 (2004).
Qiu, Z. & Ghosh, A. A calcium-dependent switch in a CREST-BRG1 complex regulates activity-dependent gene expression. Neuron 60, 775–787 (2008).
Edgar, R., Domrachev, M. & Lash, A.E. Gene Expression Omnibus: NCBI gene expression and hybridization array data repository. Nucleic Acids Res. 30, 207–210 (2002).
McQuown, S.C. et al. HDAC3 is a critical negative regulator of long-term memory formation. J. Neurosci. 31, 764–774 (2011).
Vecsey, C.G. et al. Histone deacetylase inhibitors enhance memory and synaptic plasticity via CREB:CBP-dependent transcriptional activation. J. Neurosci. 27, 6128–6140 (2007).
Babayan, A.H. et al. Integrin dynamics produce a delayed stage of long-term potentiation and memory consolidation. J. Neurosci. 32, 12854–12861 (2012).
Chen, Y. et al. Impairment of synaptic plasticity by the stress mediator CRH involves selective destruction of thin dendritic spines via RhoA signaling. Mol. Psychiatry published, online doi:10.1038/mp.2012.17 (13 March 2012)..
Geisler, S., Heilmann, H. & Veh, R.W. An optimized method for simultaneous demonstration of neurons and myelinated fiber tracts for delineation of individual trunco-and palliothalamic nuclei in the mammalian brain. Histochem. Cell Biol. 117, 69–79 (2002).
Colgin, L.L., Jia, Y., Sabatier, J.-M. & Lynch, G. Blockade of NMDA receptors enhances spontaneous sharp waves in rat hippocampal slices. Neurosci. Lett. 385, 46–51 (2005).
Lawlor, P.A. et al. Novel rat Alzheimer's disease models based on AAV-mediated gene transfer to selectively increase hippocampal Abeta levels. Mol. Neurodegener. 2, 11 (2007).
Pfaffl, M.W. A new mathematical model for relative quantification in real-time RT-PCR. Nucleic Acids Res. 29, e45 (2001).
Pfaffl, M.W. et al. Real-time RT-PCR quantification of insulin-like growth factor (IGF)-1, IGF-1 receptor, IGF-2, IGF-2 receptor, insulin receptor, growth hormone receptor, IGF-binding proteins 1, 2 and 3 in the bovine species. Domest. Anim. Endocrinol. 22, 91–102 (2002).
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.
The authors declare no competing financial interests.
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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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