Neurodevelopmental models of transcription factor 4 deficiency converge on a common ion channel as a potential therapeutic target for Pitt Hopkins syndrome

ABSTRACTThe clinically pleiotropic gene, Transcription Factor 4 (TCF4), is a broadly expressed basic helix-loop-helix (bHLH) transcription factor linked to multiple neurodevelopmental disorders, including schizophrenia, 18q deletion syndrome, and Pitt Hopkins syndrome (PTHS). In vivo suppression of Tcf4 by shRNA or mutation by CRISPR/Cas9 in the developing rat prefrontal cortex resulted in attenuated action potential output. To explain this intrinsic excitability deficit, we demonstrated that haploinsufficiency of TCF4 lead to the ectopic expression of two ion channels, Scn10a and Kcnq1. These targets of TCF4 regulation were identified through molecular profiling experiments that used translating ribosome affinity purification to enrich mRNA from genetically manipulated neurons.Using a mouse model of PTHS (Tcf4+/tr), we observed a similar intrinsic excitability deficit, however the underlying mechanism appeared slightly different than our rat model - as Scn10a expression was similarly increased but Kcnq1 ...