Oxytocin and gabaergic rescue of benzodiazepine resistance in social mammals - neurological medical emergencies of hyperexcitability, such as anxiety and seizures, rely upon fast acting and reliable…

The National Institute of Neurological Disorders and Stroke awarded the Research Foundation of the City University of New York (College of Staten Island) $530,156 on September 1, 2026, under the Extramural Research Programs in the Neurosciences and Neurological Disorders program (CFDA 93.853).

The award funds research on oxytocin and GABAergic rescue of benzodiazepine resistance in social mammals. The project investigates why benzodiazepines fail in roughly half of patients with neurological medical emergencies such as anxiety and seizures, hypothesizing that an element of social nesting—oxytocin—can reverse impaired neuronal chloride regulation and correct benzodiazepine resistance. The research focuses on the African naked mole-rat, a species that natively expresses a neuronal potassium chloride cotransporter variant (KCC2-R952H) occurring at higher rates in humans with autism, epilepsy, and schizophrenia. Testing will employ immunohistochemistry, imaging, and electrophysiology conducted by undergraduate and graduate research assistants, comparing the variant across two species that harbor KCC2-952 mutations. The work aims to improve benzodiazepine efficacy in medical emergencies and enhance the research environment at the primarily undergraduate-serving public institution.

Performance occurs in Staten Island, New York. The period of performance runs from September 1, 2026, through August 31, 2030.

Oxytocin and gabaergic rescue of benzodiazepine resistance in social mammals - neurological medical emergencies of hyperexcitability, such as anxiety and seizures, rely upon fast acting and reliable first-line treatments to inhibit brain activity and restore control. Yet, current first line treatments, benzodiazepines, do not work in roughly one half of patients. This lack of benzodiazepine efficacy is a symptom of an underlying failure to maintain neuronal transmembrane chloride balance because of developmental, genetic, or environmental factors. Previously we discovered a genetic predisposition for neuronal chloride dysregulation in the african naked mole-RAT, a eusocial and fossorial rodent which natively expresses a variant of the neuronal potassium chloride cotransporter (KCC2-R952H) that occurs at higher rates in humans with autism, epilepsy, and schizophrenia. Naked mole-rats show benzodiazepine resistance, and susceptibility to anxiety and seizures, but only when they are removed from the colony nest environment. Based on this, we have developed the hypothesis that an element of social nesting, oxytocin, can reverse impoverished KCC2 function and correct the benzodiazepine resistance predisposition to protect against anxiety and seizures. This hypothesis will be tested across two species which natively harbor variants at the KCC2-952 locus using tools in immunohistochemistry, imaging and in vitro and in vivo, electrophysiology by a team of undergraduate and graduate research assistants. In addition to enhancing the research environment at a primarily undergraduate serving public institution in the city of new york, this work will have important implications for understanding the requirements to improve benzodiazepine efficacy in medical emergencies.