Pathway-Specific Control of Striatal Neuron Vulnerability by Corticostriatal Cannabinoid CB1 Receptors

Abstract

The vast majority of neurons within the striatum are GABAergic medium spiny neurons (MSNs), which receive glutamatergic input from the cortex and thalamus, and form two major efferent pathways: the direct pathway, expressing dopamine D₁ receptor (D₁R-MSNs), and the indirect pathway, expressing dopamine D₂ receptor (D₂R-MSNs). While molecular mechanisms of MSN degeneration have been identified in animal models of striatal damage, the molecular factors that dictate a selective vulnerability of D₁R-MSNs or D₂R-MSNs remain unknown. Here, we combined genetic, chemogenetic, and pharmacological strategies with behavioral and neurochemical analyses, and show that the pool of cannabinoid CB₁ receptor (CB₁R) located on corticostriatal terminals efficiently safeguards D₁R-MSNs, but not D₂R-MSNs, from different insults. This cell-specific response relies on the regulation of glutamatergic signaling, and is independent from the CB₁R-dependent control of astroglial activity in the striatum. These findings define cortical CB₁R as a pivotal synaptic player in dictating a differential vulnerability of D₁R-MSNs versus D₂R-MSNs, and increase our understanding of the role of coordinated cannabinergic-glutamatergic signaling in establishing corticostriatal circuits and its dysregulation in neurodegenerative diseases.

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