Abstracts

Rationale: Epilepsy is a common and debilitating neurological disorder and persons with epilepsy often suffer from comorbid conditions, such as depression. There is a strong clinical association between epilepsy and the development of depression. Also, persons with a history of depression or suicidality have a higher risk of developing epilepsy, suggesting the existence of common pathogenic mechanisms that facilitate the occurrence of one in the presence of the other. Thus, amechanistic understanding of these comorbidities and the development of effective therapeutics are major unmet medical needs. Despite the wealth of animal models of epilepsy that also show neuropsychiatric disorder-related phenotypes, it is difficult to study individual molecular and cellular mechanisms underlying comorbidities because the causative cell types are ambiguous, and molecular and cellular alterations occurring in conventional models of acquired epilepsy are likely too complex. Thus, a cell-type-specific monogenic model displaying comorbid conditions is beneficial for identifying disease mechanisms as well as for the screening and development of novel therapeutic agents. Parvalbumin (PV)-expressing interneurons are highly implicated in the pathophysiology of both epilepsy and depression. We chose Supt6h as a novel molecular target because it is a binding partner of RNA polymerase II and Iws1, an RNA polymerase II-associated elongation factor. A recent GWAS study implicates Iws1 as a potential gene associated with suicide attempt and mood disorders. Supt6h was also found to be an interactor of S100a10, alterations of which are highly implicated in major depressive disorder and antidepressant actions. In addition, the genetic variation of RNA polymerase II is implicated in developmental abnormalities with epilepsy. We hypothesized that the conditional deletion of Supt6h in PV-interneurons would generate a mouse model of epilepsy and depression comorbidities. 

Methods: WT and PV neuron-selective Supt6h hetero- and homozygous KO mice were generated. We performed EEG analyses, immunohistochemistry for PV expression and behavioral tests to assess comorbidities.

Results: PV-Supt6h homozygous KO mice displayed a convulsive seizure phenotype and died at around 5 weeks of age.  PV-Supt6h heterozygous KO mice did not display a convulsive seizure phenotype but showed subclinical electrographic seizures. PV-Supt6h heterozygous KO mice also displayed reduced grooming in the sucrose splash test and a significant deficit in nesting behavior, two phenotypes of relevance to depression. Immunoreactivity for PV was significantly decreased in PV-Supt6h heterozygous and homozygous KO mice compared to WT controls.

Conclusions: Our data indicate that a Supt6h KO in PV neurons causes abnormalities in well-being and self-care behavior, a decreast of PV immunoreactivity, and epileptic seizures.  Our results further indicate that heterozygous PV-Supt6h KO mice might be useful to study comorbidity mechanisms and to identify innovative therapeutic targets for epilepsy and neuropsychiatric comorbidities. 

Funding: AES Seed Grant