Together, these findings support the hypothesis that in schizophrenia, a lower density of CB1Rs could be an adaptation that partially compensates for upstream reductions in GAD67-mediated GABA synthesis (5,6) by reducing the 2-AG-mediated block of GABA release from the terminals of CB1R/CCK-containing neurons. By enhancing GABA release specifically from the terminals of those neurons, this homeostatic adaptation could contribute to a partial, albeit insufficient, normalization of neural network activity necessary for working memory function (20). However, although GAD67+/− mice nicely model the magnitude of reduced PFC GAD67 mRNA levels in schizophrenia, this illness is not defined by a single gene heterozygous null mutation and, consequently, other potential pathogenetic processes must be considered. For example, deficits in GABA-related transcripts in schizophrenia may alternatively reflect impaired development of specific classes of GABA neurons due to other upstream pathogenetic sources (15) or perhaps a compensatory downregulation of inhibitory signaling mechanisms in response to deficient excitation in the disorder (21). Furthermore, the extent to which the genetic manipulation of GAD67 expression in mice recapitulates the disease process of schizophrenia requires knowledge of other factors, such as when in development the deficit in GAD67 arises in schizophrenia.
