My research investigates the role of selenoproteins in nervous system development and function. Selenoproteins are a unique family of proteins, characterized by the co-translational incorporation of selenium as selenocysteine, that play key roles in defense against oxidative stress. Current studies are focused largely upon selenoprotein function in two discrete populations of neurons, parvalbumin-(PV) inhibitory neurons and leptin receptor-expressing neurons of the hypothalamus.
PV-interneurons are a class of GABAergic inhibitory neurons with fast-spiking properties that synchronize activity among neuronal populations. Due to their fast-spiking properties, these neurons are highly metabolically active and especially prone to redox imbalance. Moreover, dysfunction of PV-interneuron networks has been implicated in autism, epilepsy, and schizophrenia. Selenoprotein synthesis is essential for PV interneurons, as PV interneurons fail to develop in transgenic mice where selenoprotein synthesis is conditionally disrupted in neurons, PV interneurons. Our recent studies have investigated transgenic mice lacking functional genes for both selenoprotein P, the putative selenium transport protein, and selenocysteine lyase, an enzyme involved in selenium recycling. These mice exhibit reduced survival, impaired motor coordination, neurodegeneration in auditory and motor-related brain regions, and audiogenic seizures. The audiogenic seizures appear to stem from reduced GABAergic inhibition in the inferior colliculus, as PV-interneuron density and GAD67 immunoreactivity are greatly reduced. We have also found that our male transgenic mice are more susceptible to neurodegeneration and neurobehavioral deficits than their female counterparts. Finally, pre-pubescent castration of male transgenic mice was demonstrated to prevent behavioral deficits, attenuate neurodegeneration, and increase brain selenoprotein levels.
In addition, efforts are currently underway to decipher the contribution of selenoprotein M (SelM) to hypothalamic leptin signaling. We have previously reported that SelM KO mice are obese, with elevated circulating leptin levels and diminished hypothalamic leptin sensitivity. Furthermore, we have found that SelM is present in leptin receptor-expressing neurons of the arcuate hypothalamus. Elevated oxidative stress in these neurons has been demonstrated to diminish leptin signaling and promote obesity. We hypothesize that SelM serves to promote redox balance and nutrient sensing in these neurons.