Tcf4 Deficiency Causes Recurrent Seizures in Mice.

Publication date: Jul 04, 2025

Transcription factor 4 (TCF4) is essential for the normal development and function of the central nervous system. Haploinsufficiency of TCF4 due to deletions or mutations causes Pitt-Hopkins Syndrome (PTHS), a lifelong neurodevelopmental disorder characterized by seizures, autism, and intellectual disability. Previous studies have shown that various mutations, including deletion of exon 4 in the mouse Tcf4 gene in neural progenitors, neurons, or oligodendrocytes, did not reproduce the seizure phenotype. Here, we report that mice with a heterozygous deletion of Tcf4 in Aldehyde Dehydrogenase 1 Family Member L1 (Aldh1l1)-expressing cells-which resulted in approximately 60% reduced Tcf4 expression in astrocytes and a 35% reduction in other cell types, including neurons and oligodendrocytes-developed astrogliosis as early as postnatal day 4, followed by severe recurrent seizures beginning at three months of age or later, and exhibited shortened lifespans. Additionally, these mice showed increased neuronal activity in the cortex, hippocampus, amygdala, and hypothalamus in adulthood. Furthermore, single-nucleus RNA sequencing revealed widespread gene expression changes, including genes associated with epilepsy, in excitatory neurons, inhibitory neurons, astrocytes, and oligodendrocytes in our PTHS mouse model compared to wild-type controls. Overall, this is the first report of a PTHS mouse model exhibiting seizures, providing a valuable tool to investigate the mechanisms underlying PTHS pathogenesis and to develop therapies for PTHS and its associated epilepsy.

Semantics

Original Article