mGlu₇ expression is upregulated by Tcf4 deficiency in a model of Pitt Hopkins syndrome

Pitt-Hopkins syndrome (PTHS) is a rare neurodevelopmental disorder caused by de novo mutations in the Transcription Factor 4 (TCF4) gene. Clinically, phenotypes of PTHS involve motor and cognitive domains as well as epilepsy and breathing abnormalities. These phenotypes exhibit significant overlap with another disorder, Rett syndrome (RTT), caused by mutations in the Methyl-CpG-Binding Protein 2 (MECP2) gene. We have shown that expression of metabotropic glutamate receptor 7 (mGlu₇) is significantly decreased in brain samples of patients with RTT, and we showed therapeutic potential of increasing mGlu₇ activity in RTT model mice using a small molecule positive allosteric modulator (PAM) with mGlu₇ activity. A recent study mapped TCF4 binding sites throughout the human genome and identified a TCF4 binding site in the Metabotropic Glutamate Receptor 7 (GRM7) gene. Symptom overlap, as well as the potential regulation of GRM7 by TCF4, led us to profile mGlu₇ expression in the brains of Tcf4^+/- animals. These studies identified an unexpected upregulation of the receptor at both the mRNA and protein level in multiple brain areas, with brain region-specific differences in the regulation of the two main mGlu₇ splice variants, suggesting that these two splice variants may be distinctly regulated in the context of Tcf4 heterozygosity.