Jeremy C. Petravicz, Ph.D. - US grants

DESCRIPTION (provided by applicant): Neuronal networks in the visual cortex integrate synaptic inputs to make complex outputs that underlie vision. Most studies of visual cortical function and development have focused exclusively on neurons. Astrocytes are a non-neuronal cell type in the brain that are at least as numerous as neurons and perform multiple metabolic and support functions. Astrocytes perform several functional roles that can affect the processing of sensory information, evidence for which can be found in the somatosensory cortex, olfactory bulb, and spinal cord. In the primary visual cortex, orientation tuning and regulation of response gain are critical features of vision. The mechanisms underlying these features involve interplay between excitation and inhibition to establish the response properties of a given neuron. I hypothesize that astrocytes contribute importantly to this interplay. Among their functions is the removal of neurotransmitters from the synapse during activity. One of the most influential transporter systems expressed by astrocytes is the glutamate transporter system, which removes synaptically released glutamate from the synaptic cleft to curtail the time course of transmission and reduce the activation of extrasynaptic receptors or adjacent synapses. This serves as a mechanism to reduce excitation that may be important in visual cortex function. Preliminary evidence suggests that glutamate transporters are a critical component in the maintenance of visual processing, as inhibition of transporters prolongs neural responses and broadens the orientation tuning of visual cortex neurons in vivo. Glutamate transporters are also critical to the development of brain circuits, with evidence existing for abnormal cortical development when there is either increased or decreased glutamate transport. Dysregulation of glutamate transporters has been implicated in neurodevelopmental disorders such as schizophrenia and autism. Therefore, studies into astrocytic regulation of extracellular glutamate could provide valuable insight into neuronal network development and function through glutamate transporters. This proposal details an experimental approach that utilizes electrophysiology and state of the art in vivo imaging techniques to determine the role of astrocyte glutamate transporters in visual cortex function and development. First, the effects of glutamate transporter inhibition on neuronal transmission in primary visual cortex of mice will be assessed using slice electrophysiology experiments. Second, the role of glutamate transporters in cortical development and experience-dependent plasticity will be investigated using the well- established paradigm of monocular deprivation and mice that are mutant for astrocyte transporter genes. Finally, in vivo imaging and electrophysiology will be used to examine how inhibition of glutamate transporter activity alters orientation tuning and response gain of visual cortex neurons. The combination of these methods will allow for a critical assessment of how astrocytes modulate neural activity through glutamate transporters and influence visual cortex development and processing. PUBLIC HEALTH RELEVANCE: Astrocyte glutamate transporter dysfunction has been implicated in a number of neurodegenerative and neuropsychiatric disorders, such as schizophrenia and autism. By studying and understanding the role of astrocyte glutamate transporters during cortical development and in modulating network activity in the visual cortex, potential drug targets for treatment of glutamatergic signaling disorders.