Intellectual disorders are characterized by impairments in cognition, social behaviors, and communication. Recent human exome sequencing studies have identified subunits of the polymorphic BAF complexes (mammalian SWI/SNF chromatin remodeling complex) that are frequently mutated in sporadic mental retardation and sporadic autism. Moreover, de novo mutations in various subunits of neuron-specific Brg1-associated factor (nBAF) nucleosome remodeling complex have been implicated in Coffin-Siris and Nicolaides-Baraitser syndromes, both of which are associated with intellectual disability. Together, these studies suggest that nBAF function is necessary for normal cognitive function. Nucleosome remodeling complexes modify chromatin structure and regulate expression by repositioning nucleosomes at the promoters of genes. Why disturbances to chromatin remodeling via mutations in BAF complexes result in cognitive dysfunction is unknown. Although an important topic in other fields (e.g. yeast genetics and cancer), nucleosome remodeling has received little attention in neuroscience. However, a major discovery was the identification of the first neuron-specific BAF complex, which was subsequently found to regulate gene expression required for the conversion of precursor cells into terminally differentiated neurons. Importantly, the nBAF complex has a subunit, BAF53b, which participates in making nBAF neuron- specific. This subunit is both neuron and nBAF complex specific, making it an ideal target for investigating the potential contributions of nBAF t synaptic physiology and behavior. Building on this point, we propose to test the hypothesis that BAF53b, after playing a key role in neuronal fate decisions during development, continues to regulate gene expression and does so in a manner critical to adult plasticity and memory. We propose three specific aims to test this hypothesis.
In Aim 1, we will use genetically modified mice to examine the role of BAF53b in long-term memory.
In Aim 2, we will examine the role of BAF53b in long-term potentiation, a form of synaptic plasticity.
In Aim 3, we will use next generation sequencing, RNA seq, to determine what gene expression profiles are being regulated by BAF53b during memory consolidation. Together, the work under these aims will elucidate the contributions of BAF53b, and the nBAF complex in general, to memory processes, and thereby significantly contribute to the understanding of how mutations in the complex lead to cognitive impairments in humans.

Public Health Relevance

Intellectual disorders are characterized by impairments in cognition, social behaviors, and communication. In 2012, several mutations in humans were identified in a new protein complex implicating nucleosome remodeling, an epigenetic mechanism, in several intellectual disorders. This research proposal provides a unique approach to understand how mutations in this newly identified complex give rise to cognitive impairments associated with intellectual disorders.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Research Project (R01)
Project #
Application #
Study Section
Developmental Brain Disorders Study Section (DBD)
Program Officer
Beckel-Mitchener, Andrea C
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of California Irvine
Other Basic Sciences
Schools of Arts and Sciences
United States
Zip Code
Wang, Weisheng; Le, Aliza A; Hou, Bowen et al. (2018) Memory-Related Synaptic Plasticity Is Sexually Dimorphic in Rodent Hippocampus. J Neurosci 38:7935-7951
Shu, Guanhua; Kramár, Enikö A; López, Alberto J et al. (2018) Deleting HDAC3 rescues long-term memory impairments induced by disruption of the neuron-specific chromatin remodeling subunit BAF53b. Learn Mem 25:109-114
Alaghband, Yasaman; Kramár, Enikö; Kwapis, Janine L et al. (2018) CREST in the Nucleus Accumbens Core Regulates Cocaine Conditioned Place Preference, Cocaine-Seeking Behavior, and Synaptic Plasticity. J Neurosci 38:9514-9526
Kwapis, Janine L; Alaghband, Yasaman; Kramár, Enikö A et al. (2018) Epigenetic regulation of the circadian gene Per1 contributes to age-related changes in hippocampal memory. Nat Commun 9:3323
López, Alberto J; Jia, Yousheng; White, André O et al. (2018) Medial habenula cholinergic signaling regulates cocaine-associated relapse-like behavior. Addict Biol :
Alaghband, Yasaman; Kwapis, Janine L; López, Alberto J et al. (2017) Distinct roles for the deacetylase domain of HDAC3 in the hippocampus and medial prefrontal cortex in the formation and extinction of memory. Neurobiol Learn Mem 145:94-104
Hemstedt, Thekla J; Lattal, K Matthew; Wood, Marcelo A (2017) Reconsolidation and extinction: Using epigenetic signatures to challenge conventional wisdom. Neurobiol Learn Mem 142:55-65
Kwapis, Janine L; Alaghband, Yasaman; López, Alberto J et al. (2017) Context and Auditory Fear are Differentially Regulated by HDAC3 Activity in the Lateral and Basal Subnuclei of the Amygdala. Neuropsychopharmacology 42:1284-1294
López, Alberto J; Kramár, Enikö; Matheos, Dina P et al. (2016) Promoter-Specific Effects of DREADD Modulation on Hippocampal Synaptic Plasticity and Memory Formation. J Neurosci 36:3588-99
Kleeman, Elise; Nakauchi, Sakura; Su, Hailing et al. (2016) Impaired function of ?2-containing nicotinic acetylcholine receptors on oriens-lacunosum moleculare cells causes hippocampus-dependent memory impairments. Neurobiol Learn Mem 136:13-20

Showing the most recent 10 out of 20 publications