Glutamate hypothesis of schizophrenia

The glutamate hypothesis of schizophrenia models the subset of pathologic mechanisms linked to glutamatergic signaling. The hypothesis was initially based on a set of clinical, neuropathological, and, later, genetic findings pointing at a hypofunction of glutamatergic signaling via NMDA receptors. While thought to be more proximal to the root causes of schizophrenia, it does not negate the dopamine hypothesis, and the two may be ultimately brought together by circuit-based models. The development of the hypothesis allowed for the integration of the GABAergic and oscillatory abnormalities into the converging disease model and made it possible to discover the causes of some disruptions.

Like the dopamine hypothesis, the development of the glutamate hypothesis developed from the observed effects of mind-altering drugs. However, where dopamine agonists can mimic positive symptoms with significant risks to brain structures during and after use, NMDA antagonists mimic some positive and negative symptoms with less brain harm. Likely, both dopaminergic and glutaminergic abnormalities are implicated in schizophrenia, from a profound alteration in the function of the chemical synapses, as well as electrical synaptic irregularities. These form a portion of the complex constellation of factors, neurochemically, psychologically, psychosocially, and structurally, which result in schizophrenia.

Alteration in the expression, distribution, autoregulation, and prevalence of specific glutamate heterodimers alters relative levels of paired G proteins to the heterodimer-forming glutamate receptor in question.

Namely: 5HT2A and mGlu2 form a dimer which mediates psychotomimetic and ethenogenin effects of psychedelics; as such this receptor is of interest in schizophrenia. Agonists at either constituent receptor may modulate the other receptor allosterically; e.g. glutamate-dependent signaling via mGlu2 may modulate 5HT2A-ergic activity. Equillibrium between mGlu2/5HT2A is altered against tendency towards of psychosis by nueroleptic-pattern 5HT2A antagonists and mGlu2 agonists; both display antipsychotic activity. AMPA, the most widely distributed receptor in the brain, is a tetrameric ionotropic receptor; alterations in equillibrium between constituent subunits are seen in mGlu2/5HT2A antagonist (antipsychotic) administration- GluR2 is seen to be upregulated in the PFC while GluR1 downregulates in response to antipsychotic administration.

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