Functions and mechanisms of a subpopulation of striatal astrocytes

ABSTRACT Astrocytes are ubiquitous CNS glial cells that make extensive contacts with neurons. Astrocytes serve diverse roles, including ion homeostasis, neurotransmitter clearance, synapse formation/removal, synaptic modulation, and contributions to neurovascular coupling. Astrocytes are widely implicated in disease and in regulating animal behaviour. Astrocytes are thus critical components of neural circuits and their behavioral outputs. How astrocytes perform such varied physiological roles is a topic of intense worldwide investigation with many fascinating open questions. An exciting discovery made by us and others over the last few years is that astrocytes are heterogeneous, displaying CNS region and neural circuit-specific properties and functions. Exploring the molecular basis and function of astrocyte diversity within specific neural circuits is emerging as an important, innovative research frontier. One outstanding open task is to understand functions of molecularly defined astrocytes in specific CNS areas and to determine how they regulate neural circuits and contribute to behaviors associated with those nuclei. We address this topic for a specific population of Crym+ (protein: μ-crystallin) striatal astrocytes in relation to motor and goal-directed behavior. Interestingly, Crym is downregulated in postmortem striatal tissue in some basal ganglia diseases, implying that understanding how these astrocytes regulate neural circuits physiologically may, in the long term, inform about disease mechanisms. However, almost nothing is known physiologically about either μ-crystallin or about Crym+ striatal astrocytes in the CNS. Based on unexpected and exciting preliminary data, we hypothesize that striatal astrocytes defined by Crym regulate essential astrocyte-neuron interactions within CM striatal microcircuits that control motor and goal-directed behavior. The preliminary data to support this hypothesis are compelling and new. Specific Aim 1 will evaluate how striatal astrocyte-specific CRISPR/Cas9-mediated Crym deletion affects MSNs and astrocytes. Specific Aim 2 will study MSN activity in vivo during behavior following striatal astrocyte Crym deletion. Specific Aim 3 will explore molecular mechanisms of striatal astrocyte Crym (μ-crystallin) in relation to striatal-dependent behaviors. Completion of these aims will advance markedly our understanding of striatal astrocyte-neuron interaction mechanisms and of μ-crystallin. We believe our studies will also be paradigmatic for understanding astrocyte diversity within neural circuits and the functions that such specializations serve in relation to the striatum and the basal ganglia circuitry.