Glutamate Hypothesis of Schizophrenia - GPCRs and Schizophrenia

GPCRs and Schizophrenia

We know that hypofunctioning glutamate receptors are a contributing factor in developing schizophrenia.(Mechri, A 2001) Alterations in the expression, distribution, autoregulation,(Catapano, L Manji, H, 2006) prevalence of specific heterodimers,(Gonzales, 2012) and relative levels of G proteins, specifically lowered levels of the i isomorph,(F Odaka, T.J Crow, G.W Roberts) all can result in an altered NMDA function. The primary contributor to schizophrenia is a relative deficit of presynaptic glutamate receptors to the postsynaptic receptors. Specifically, group II is indicated in this disorder, given that mGlu2/3 agonists have been found useful in the treatment of both positive and negative symptoms. However, all regulatory neurotransmitters are involved, as every metabotropic receptor has potential to alter glutaminergic function.(Sugai, 2006) Specifically, 5-HT has an extraordinarily wide role in modulatory processes of the brain, as such, it is highly implicated in all CNS function. In addition, CB1 plays a global inhibitory role, serving to inhibit the release of all neurotransmitters. In addition, CB1 is one of the most widely distributed receptors in the brain, thus, downregulation of this receptor will increase global chemical synaptic activity. No difference in expression or distribution is observed, but when the CB1 receptor develops a tolerance, 2-AG(full) cannot exert its full inhibitory effects on GABA and glutamate release. A deficit in endocannobinoid metabolism, or excess catabolism, as well as heavy cannabis use, will deregulate global chemical transmission.

This is the key in schizophrenia: the fact this deregulates glutamate carboxylase expression, which acts to downregulate reelin production, the crucial mediator of neurogenesis. Specifically, the reelin expressing cajal-retziu cells are of interest. These cells are a crucial component of corticocorical transmission, due to their long, nearly horizontal axons, multiple synapses, and consistent termination on spiny pyramidal neurons. These allow for interlayer communication over a wider area than those without, e.g. chimpanzees. This is the part of the neurological system which is most different, and the part of the genome which is most "accelerated" vs them. This would indicate that this is a necessary factor for the development of the so-called speech centers of the brain, Wernickie's and Broca's areas. Also, a deficit in reelin activity is associated with cortical developmental retardation. These neurons also express 5-HT3 significantly, which is the only serotonergic ligand gated ion channel. Presynaptically, they act to regulate neurotransmitter release, mediating the frequency and strength of tonic firing in connected neurons. This is likely the mechanism through which they mediate long term potentiation. A deficit in this activity would alter plasticity significantly, contributing to the illnesses of bipolar disorder and schizophrenia.