Geon The Roles of 5-HT2A Receptors and mGluR2 in Schizophrenia



The hypoactive pyramidal neurons in cortical layer 3 (L3) may result in cognitive impairment while hyperactivity of L5 pyramidal neurons could lead to positive symptoms (psychosis) of schizophrenia (Paper 25). The hypoactivity of L3 pyramidal neurons does not necessarily lead to hyperactivity of L5 pyramidal neurons. Additional abnormalities are required to cause psychosis. This paper shows that hyperactive glycogen synthase kinase 3 (GSK-3) could be a major abnormality involved in psychosis, based on the studies of psychedelics, which are a class of hallucinogenic drugs that target primarily 5-HT2A receptors (5-HT2AR) in L5. However, not all 5-HT2AR agonists are hallucinogens. González-Maeso et al. (2007) demonstrated that their major difference could lie in the capacity of hallucinogens to induce the Gi/o pathway. This notion is supported by the finding that mGluR2, which is known to mediate the Gi/o pathway, colocalizes with 5-HT2AR at the postsynaptic density of cortical pyramidal neurons. The Gi/o pathway can inhibit protein kinase A, resulting in hyperactive GSK-3. In support of this mechanism, GSK-3 has been shown to be the convergent target of most atypical antipsychotics.


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