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

The 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). suppression of 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, and . 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 (), we observed a similar intrinsic excitability deficit, however the underlying mechanism appeared slightly different than our rat model - as expression was similarly increased but expression was decreased. Here, we show that the truncated TCF4 protein expressed in our PTHS mouse model binds to wild-type TCF4 protein, and we suggest the difference in expression levels between these two rodent models appears to be explained by a dominant-negative function of the truncated TCF4 protein. Despite the differences in the underlying molecular mechanisms, we observed common underlying intrinsic excitability deficits that are consistent with ectopic expression of . The converging molecular function of TCF4 across two independent rodent models indicates SCN10a is a potential therapeutic target for Pitt-Hopkins syndrome.