| Cannabis use is associated with both impaired cognitive
functions, including working memory, and an increased risk of schizophrenia.
In addition, schizophrenia is characterized by impairments in working memory
that are due, at least in part, to reduced GABA neurotransmission in the
dorsolateral prefrontal cortex (DLPFC). The cannabinoid 1 receptor (CB1R)
is highly expressed in the DLPFC, is contained in the axon terminals of
a subpopulation of CCK-containing, perisomatic-targeting GABA neurons, and
when activated, suppresses the release of GABA. In order to determine the
potential relationship between CB1 receptor signaling and altered GABA neurotransmission
in schizophrenia, we evaluated CB1 receptor mRNA and protein expression
in the DLPFC from 23 pairs of schizophrenia and age-, sex-, and postmortem
interval-matched comparison subjects. CB1 mRNA levels (panels A, B), assessed
by in situ hybridization, were significantly 15% lower in the subjects with
schizophrenia. Similarly, CB1 protein, assessed by radioimmunocytochemistry
(RICC; panels C, D) and standard immunocytochemistry, was significantly
decreased by 12% and 14%, respectively. Importantly, the within-pair percent
change in CB1 RICC in the subjects with schizophrenia strongly correlated
with the within-pair percent change in CB1 mRNA expression, indicating that
changes in CB1 protein paralleled the changes in CB1 mRNA (panel E). CB1
mRNA expression was not changed in the DLPFC of monkeys chronically exposed
to haloperidol or olanzapine, and neither CB1 mRNA or protein levels were
affected by potential confounding factors in the subjects with schizophrenia.
Finally, differences in CB1 mRNA levels were significantly correlated with
those in glutamic acid decarboxylase (GAD67) and cholecystokinin (CCK) mRNA
levels in the same subjects with schizophrenia. This combination of findings
suggests the testable hypothesis that reduced CB1R mRNA and protein in schizophrenia
represent a compensatory mechanism to increase GABA transmission from perisomatic-targeting
CCK interneurons with impaired GABA synthesis (panel F). |
