UC Riverside

Developmental factors involved in schizophrenic pathology are known to exist, but complex chemical interactions during critical stages of brain development are unclear. Environmental and genetic factors contribute to the development of cortical brain circuits and disruption during specific critical times in development could have lifelong consequences. N-methyl-D-aspartate receptors (NMDARs) are of critical importance for synaptic formation as well as synaptic plasticity throughout the lifespan. Hypofunctioning NMDARs have been implicated in schizophrenic patients and have been extensively used as the basis of animal models to study schizophrenia in a lab environment. Here we use a developmental model induced by drugs that block NMDARs during early stages of postnatal development in order to model schizophrenia in mice. These mice have shown permanent reductions in endocannabinoid (eCB) signaling in the medial prefrontal cortex (mPFC). These findings emphasize a possible involvement of eCB signaling in the development of schizophrenia. eCBs are unusual in that they act retrogradely at the synapse and are released on demand under high levels of post synaptic activation. Since the overall effects of eCBs at the synapse are inhibitory, it has been suggested that eCBs may play an important role in maintaining a nominal level of neuronal activation in the cortex. This also led us to investigate a well-known risk factor of schizophrenia, adolescent cannabis abuse. Cannabis contains Δ9-tetrahydrocannabinol (THC) which directly activates cannabinoid receptors in the brain. Prolonged exposure to cannabis during adolescence has been speculated to have long-term effects in some people lasting into adulthood. An adolescent cannabis abuse model induced by a specific agonist of the primary cannabinoid receptor (CB1R) in the brain shows permanent reduction in the eCB system signaling including impaired eCB-dependent synaptic plasticity and CB1R function. In addition, the cannabis abuse model shows deficiency in a function of another presynaptic receptor involved in control of presynaptic release, metabotropic glutamate receptor 2/3 (mGluR2/3). CB1Rs and mGluR2/3 receptors both share the same intracellular signaling pathways which suggest that the critical maladaptation underlying the etiology of psychosis may involve signaling mediated by presynaptic metabotropic receptors or downstream processes. These data open a new avenue for understanding and treatments of schizophrenia taking into account important developmental factors.