GABAergic Interneuron Development and Function Is Modulated by the Tsc1 Gene

Abstract

Tuberous sclerosis complex (TSC) is a genetic disease with severe neurologic and psychiatric manifestations including epilepsy, developmental delay, and autism. Despite much progress in defining abnormal signaling pathways including the contribution of increased mTORC1 signaling, specific abnormalities that underlie the severe neurologic features in TSC remain poorly understood. We hypothesized that epilepsy and autism in TSC result from abnormalities of γ-aminobutyric acidergic (GABAergic) interneurons. To test this hypothesis, we generated conditional knockout mice with selective deletion of the Tsc1 gene in GABAergic interneuron progenitor cells. These interneuron-specific Tsc1 conditional knockout (CKO) mice have impaired growth and decreased survival. Cortical and hippocampal GABAergic interneurons of CKO mice are enlarged and show increased mTORC1 signaling. Total numbers of GABAergic cells are reduced in the cortex with differential reduction of specific GABAergic subtypes. Ectopic clusters of cells with increased mTORC1 signaling are also seen suggesting impaired interneuron migration. The functional consequences of these cellular changes are evident in the decreased seizure threshold on exposure to the proconvulsant flurothyl. These findings support an important role for the Tsc1 gene during GABAergic interneuron development, function, and possibly migration.

Interneuron Dysfunction in Syndromic Autism: Recent Advances

“…The total numbers of GABAergic cells are reduced in the cortex, and ectopic clusters of cells with increased mTORC1 signaling are also seen. These findings support the hypothesis that the Tsc1 gene is involved in GABAergic interneuron development, suggesting that inhibitory cortical neurons may contribute to the pathogenesis of epilepsy and possibly autism in patients with TSC [70]. The hippocampus is a region of the brain important for learning and memory that can be involved in the generation of temporal lobe seizures [71].…”

Molecular and Neural Functions of Rai1 , the Causal Gene for Smith-Magenis Syndrome

“…In tuberous sclerosis, conditional deletion of Tsc1 in astrocytes, excitatory neurons, or inhibitory neurons all results in seizure in mice (Bateup et al, 2013; Fu et al, 2012; Uhlmann et al, 2002). In Rett syndrome, GABAergic neurons alone account for the majority of behavioral symptoms (Chao et al, 2010), with somatostatin- and parvalbumin-expressing interneurons each mediating non-overlapping Rett-like phenotypes (Ito-Ishida et al, 2015).…”

NINDS epilepsy and autism spectrum disorders workshop report

“…26 A recent mouse model with conditional knockout of the Tsc1 gene in GABAergic interneurons specifically addresses the hypothesis that functional deficiency in these interneurons leads to many hallmarks of the disease including decreased seizure threshold; the abnormalities may involve increased mTOR complex 1 (mTORC1) signaling in GABAergic neurons and point to a potential common molecular mechanism accounting for ASD and epilepsy in TSC. 27 In a rodent model of neonatal seizures, treatment with the mTORC1 inhibitor rapamycin immediately before and after seizures reversed many of the early increases in glutamatergic neurotransmission and signs of pathology including the increase in seizure susceptibility, and attenuated later-life epilepsy and autisticlike behavior. 28 FXS is caused by an expanded CGG repeat (.200) in the FMR1 gene, located on the X-chromosome, which leads to transcriptional silencing of FMR1 and loss of the fragile X mental retardation protein (FMRP).…”