Wednesday, April 24, 2024
4/24/2024
ABSTRACT Astrocytes are a key element of brain connectivity because they regulate neuronal communication at synapses. Bergmann glial cells (BGCs), a major type of astrocytes in the cerebellum, are intimately associated with excitatory glutamatergic synapses between Purkinje cell (PC) spines and parallel fibers or climbing fibers, playing a significant role in synaptic stability and long-term plasticity. BGCs express a high density of Ca2+- permeable GluA2-lacking AMPA receptors (CP-AMPARs), which are required for the maintenance of the BGC processes that ensheath PC spine synapses. Genetic deletion of CP-AMPARs results in impaired associative motor learning. Our preliminary data indicate that CP-AMPARs in BGCs are subject to dopaminergic (DAergic) modulation. Pharmacological stimulation of D1 receptors enhances CP-AMPARs-mediated currents in BGCs, and phosphorylates the GluA1 subunit at Ser845. Using transgenic mice with fluorescently-tagged D1 receptors and anterograde axonal tracing, we determined that D1 receptors are exclusively expressed in BGCs, which receive DAergic afferents from the ventral tegmental area and substantia nigra pars compacta in the midbrain. Intriguingly, D1 receptor activation also increases PC firing and locomotor activity. Based on these preliminary findings, we hypothesize that activation of D1 receptors induces insertion of CP- AMPARs in BGCs, which in turn modulates PC synaptic function. To test this hypothesis, we will use a combination of experimental approaches, including whole-cell recordings with optogenetic stimulation, immunocytochemistry, molecular biology, and pharmacology. We propose two Specific Aims: (1) characterize membrane insertion of GluA1 in Bergmann glial cells induced by DA; and (2) define the role of DAergic modulation of Bergmann glial cells in PC activity. We expect to generate conceptually novel knowledge regarding DA modulation of cerebellar circuitry function by defining the contribution of CP-AMPARs in BGCs to synaptic function in PCs. These new findings will not only deepen our understanding of DAergic function in the healthy brain, but also provide additional avenues for the development of disease-modifying therapies for motor-related neurological disorders.
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