Figure 6.

BCL11B-regulated molecular events in MSNs and CTX neurons and their likely contribution to psychiatric disorder pathogenesis. (A) Schematic of core biological processes affected by the loss of BCL11B summarizes phenotypes identified in current and previous studies, including depolarized mitochondria (green), abnormal calcium signaling, acute glutamatergic neurotransmission, disbalance in phosphatase levels, reduced cAMP-PKA signaling, and downstream dephosphorylation of DARPP32 and other targets [adapted from (11)]. (B) These core molecular changes are most prominent in MSNs compared with CTX neurons and show preferential enrichment for HD and SCZ genes, suggesting that they are likely to contribute to the pathogenesis in these disorders. In contrast, in CTX neurons, a fraction of these BCL11B-dependent phenotypes, although affected less severely, may also contribute to ASD pathogenesis. (C) In summary, we propose that MSNs play a distinct role in psychiatric disease development compared with CTX neurons, where BCL11B hypofunction acts in tandem with mHTT in HD and other risk variants in psychiatric disorders to contribute to disease pathogenesis. AMPAR, AMPA receptor; ASD, autism spectrum disorder; CTX, cortical glutamatergic; HD, Huntington’s disease; KO, knockout; mDA, midbrain dopaminergic; mHTT, mutant huntingtin; MSNs, medium spiny neurons; NDD, neurodevelopmental disorder; NMDAR, NMDA receptor; PKA, protein kinase A; SCZ, schizophrenia.