Abstracts

Rationale: BCL11A is a zinc-finger transcription factor that is predominantly expressed in the hematopoietic central nervous system. BCL11A has been highly researched in erythroid biology for its role as a fetal-to-adult hemoglobin switch but emerging evidence of the critical impact of BCL11A in neurodevelopment has increased the focus on its role in the brain. BCL11A is also one of the subunits of the BRG1/BRM-associated factor (BAF) swi/swf remodeling complex. Mutations disrupting the BAF complex, known as BAF-opathies, have been found to be involved in a wide range of neurological disorders, and importantly account for over 1% of cases of intellectual disability. Accordingly, patients with heterozygous BCL11A mutations present with ID, and the 2p15-16.1 microdeletion syndrome encompassing BCL11Ais characterized by ID, developmental delay, and dysmorphic features. In addition to ID, patients with BCL11Amutations often exhibit behavioral abnormalities such as hyperactivity and social deficits, and approximately 25% of patients also present with epilepsy. However, little is currently known about the mechanisms by which BCL11Adysfunction lead to this range of clinically challenging phenotypes.

Methods: To determine the cell type-specific contributions to the behavioral deficits associated with reduced BCL11A expression, female mice that were homozygous for a floxed Bcl11a allele were crossed with male mice that were heterozygous for Cre recombinase under the control of different cell-type specific promoters. Next, we bred male mice that were heterozygous for Cre recombinase and heterozygous for a floxed Bcl11a allele to female mice that were homozygous for a floxed Bcl11a allele to generate experimental mice. We targeted all neurons (Nestin Cre), excitatory neurons in the forebrain (Emx1 Cre), and GABAergic interneurons (Gad2 Cre). Locomotor activity and anxiety was assessed with the open field paradigm. The three chamber social interaction task was used to assess social behavior. Seizure susceptibility was evaluated with the 6 Hz seizure induction paradigm and the proconvulsant flurothyl. _x000D_
Results: We found that heterozygous deletion of BCL11A in all neurons and GABAergic interneurons resulted in hyperactivity and impaired social discrimination (N = 8-10/genotype). However, deletion of BCL11A in the excitatory neurons had no effect. Deletion of BCL11A in all neurons resulted in increased resistance to 6 Hz- and flurothyl-induced seizures (N = 9-10/genotype). We are currently performing seizure susceptibility assessments in the other mouse lines._x000D_
Conclusions: In summary, the current study has demonstrated that deletion of BCL11A from GABAergic interneurons is important for normal locomotor and social behavior. Ongoing studies will determine whether knockout of BCL11A in specific cell types alters seizure susceptibility._x000D_
Funding: Not applicable