Emerging evidence suggests that astrocytes are not passive support cells in the central nervous system, but rather play active roles in modulating neuronal activity through ionic buffering, metabolic support, and neurotransmitter uptake. Specifically, astrocytes show selective expression of a subset of neurotransmitter transporters, including GLT1 (glutamate transporter) and GAT3 (GABA transporter), which raises the possibility that astrocytes can influence neuronal activity by changing neurotransmitter uptake. Studies investigating astrocytic calcium transients have largely characterized responses using slice or in vitro preparations rather than in vivo; likewise studies into the role of neurotransmitter uptake have almost exclusively been conducted in slices in situ. Previous work has shown that large-scale astrocytic somal calcium transients can be elicited in vivo by diffuse release of neuromodulators such as acetylcholine and norepinephrine. Yet, it remains unclear how small calcium transients in the distal processes of astrocytes relate to neuronal activity and how astrocytes influence cortical sensory processing. Our lab has developed a novel visual stimulation paradigm using natural movies that reliably drives both neuronal activity and astrocytic process calcium transients in the mouse primary visual cortex.
In Aim 1, I will correlate astrocytic process calcium transients and local neuronal calcium activity simultaneously using dual-calcium imaging in vivo. Using transgenic Cre lines to restrict neuronal calcium imaging to excitatory and inhibitory neuron subpopulations, I will be able to dissect how calcium activity in astrocytes relates to specific components of the cortical circuit.
In Aim 2, I will use pharmacological and genetic manipulations of GLT1 to explore how astrocytic glutamate uptake contributes to excitatory synaptic activity during visual processing.
In Aim 3, I will use pharmacological and genetic manipulations of GAT3 to determine how astrocytic GABA uptake contributes to inhibitory synapse activity during visual processing in the cortex. By exploring astrocytic calcium activity and neurotransmitter uptake during sensory processing in the mouse visual cortex, this work will increase our understanding of astrocytic roles in cortical processing and may provide insight into disorders characterized by imbalances of excitation and inhibition such as epilepsy and schizophrenia.
Astrocyte function in the development and function of cortical circuits has been implicated in both the normal physiology and the pathology of numerous neurological disorders, such as epilepsy and autism spectrum disorders. By exploring astrocytic contribution to excitation and inhibition in neuronal circuits, known to be imbalanced in these disorders, I seek to identify novel astrocytic targets for therapeutic intervention.
