High metabolic demand of fast-spiking cortical interneurons underlying the etiology of autism

Completed

Inan, Melis

Anderson, Stewart

Weill Medical College of Cornell University

$110,500.00

2 years

Meixner Translational Postdoctoral Fellowship

New York

NY

United States

2011

City: 
New York
State/Province: 
NY
State/Province Full: 
New York
Country: 
United States

Autism spectrum disorders (ASD) are neurodevelopmental disorders that are estimated to effect 1 in 110 children. Although the etiology and biological basis of ASD is still unknown, many studies indicate that a strong and complex genetic component underlies ASD. Reports indicate a co-morbidity of mitochondrial disorders with ASD, and the association is quite high especially for ASD patients with the regressive form. Other evidence identified a role for cortical interneurons and GABAergic signaling defects in ASD. The fast-spiking, parvalbumin-expressing (PV+) subgroup of cortical interneurons is known to have tremendous metabolic demands. They also play critical roles in cortical cognitive functions by contributing to gamma band oscillations, which can synchronize neuronal circuits providing precise coordination of neuronal networks. Both the gamma band synchrony and cognitive functions can be disrupted in ASD patients. This study links these two hypotheses and proposes that symptoms of autism can be caused by mitochondrial dysfunction leading to suboptimal functioning of PV+ cortical interneurons. The research lays critical groundwork for exploring this hypothesis, by examining mitochondrial dynamics and function in PV+ interneurons, and by analyzing the roles of autism and mitochondrial related genes on PV+ interneuron activity. The in vitro and in vivo models generated in this project will provide novel insight into the cellular pathogenesis of ASD. These tools can also further be extended to generation of transgenic mice with mitochondrial defects leading to suboptimal functioning PV+ cortical interneurons. These transgenic mice can then serve as an important animal model of ASD in which potential treatments can be tested.