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Cereb Cortex. 2018 Jan 1;28(1):307-322. doi: 10.1093/cercor/bhx285.

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

Author information

1
Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Instituto Universitario de Investigación Neuroquímica (IUIN) and Department of Biochemistry and Molecular Biology I, Complutense University, 28040 Madrid, Spain.
2
Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), 28034 Madrid, Spain.
3
Instituto Universitario de Investigación Neuroquímica (IUIN) and Department of Biochemistry and Molecular Biology IV, Complutense University, 28040 Madrid, Spain.
4
INSERM and University of Bordeaux, NeuroCentre Magendie, Physiopathologie de la Plasticité Neuronale, U1215, 33077 Bordeaux, France.

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.

KEYWORDS:

Cannabinoid receptor; corticostriatal projection; huntingtin; medium spiny neuron; neuroprotection

PMID:
29121220
DOI:
10.1093/cercor/bhx285
[Indexed for MEDLINE]

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