Astrocytes are the predominate cell type in brain, closely associate with all other neural cell types, exhibit a wide array of neurotransmitter receptors, respond to neuronal activity, and release neuroactive molecules;in spite of this, we know very little about the role of these cells in physiology, behavior, or disease. A major limitation in this area is the lack of models that permit the study of astrocyte function in neural systems following sensory stimulation in living animals. To date, nearly all studies of astrocytic function have relied on pharmacological approaches to activate or inactivate signaling in these cells and to record the effects of their activity on surrounding cells in vitro or in situ. It is our view that progress in this area requires a model system where: 1) sensory input in living animals can be used to activate astrocytic signaling and, 2) behavioral readouts are available for determining the functional outcome of astrocytic signaling in vivo. To this end, we propose to use the mouse central visual pathway to investigate the role of astrocytic signaling cascades in synaptic transmission and plasticity as well as in vision.
In Specific Aim 1 we will use well-characterized slices of primary visual cortex to examine the pathways and mechanisms regulating astrocytic signaling in situ.
In Specific Aim 2 we will use in vivo imaging to determine if astrocytic calcium responses are spatially-restricted and important in the local control of vascular tone.
In Specific Aim 3 we will use in vivo imaging and genetically- modified mice to investigate the role of astrocytes in visual plasticity. Finally, in Specific Aim 4 we will genetically engineered mice to investigate the role of astrocytes in vision, a behavioral readout of sensory input into the visual cortex. Overall, the results of these studies should clarify the conditions where sensory input leads to the activation of astrocytic signaling and the role of astrocytic signaling in synaptic transmission and vision.
Astrocytes are the predominate cell type in brain, closely associate with all other neural cell types, exhibit a wide array of neurotransmitter receptors, respond to neuronal activity, and release neuroactive molecules;in spite of this, we know very little about the role of these cells in physiology, behavior, or disease. Understanding the role that astrocytes play in the visual cortex could lead to new therapeutic treatments of visual disorders.
|Khakh, Baljit S; McCarthy, Ken D (2015) Astrocyte calcium signaling: from observations to functions and the challenges therein. Cold Spring Harb Perspect Biol 7:a020404|
|Bonder, Daniel E; McCarthy, Ken D (2014) Astrocytic Gq-GPCR-linked IP3R-dependent Ca2+ signaling does not mediate neurovascular coupling in mouse visual cortex in vivo. J Neurosci 34:13139-50|