Glutamate is the primary excitatory neurotransmitter in the CNS. As such, it is crucial for the formation of any positive gain circuits within the brain. Of specific interest in this disorder are the presynaptic metabotropic receptors, which act as autoreceptors, regulating glycine and glutamate receptors, also known as NMDA receptors. NMDA receptors are unique in that they are voltage-dependent, that is, at 0 or near 0 membrane potential, they are blocked by Mg2+ ions. Only when there is a depolarization do these Ca2+ channels open. This is the primary reason for the phenomena of LTP. While this a crucial component of the plasticity system of the brain, the GABA system, and Monoamine regulatory GPCRs are the primary way this can create long-range order.

Specifically, a deficit in metabotropic glutamate receptors 1 and 5 (the primary post-synaptic receptors) results in a relative excess of the activity of the other 6 presynaptic receptors.

Interest has focused on these neurotransmitters, given the reduced function of the NMDA glutamate receptor in schizophrenia, and the ability for an exogenous agent to induce specific symptoms of this illness. This is supported by the fact that NMDA antagonists can create some of the negative symptoms of schizophrenia, e.g.

Role of Glutamate in Schizophrenia
Role of Glutamate in Schizophrenia
  • catatonia
  • thought disorder
  • typical of schizophrenic
  • psychotic patients.

However, dopaminergic drugs like methamphetamine and cocaine can cause some of the psychotic symptoms of schizophrenia, like paranoid delusions, agitation, and others.

The NMDA component has largely been suggested by abnormally low levels of glutamate receptors found in postmortem brains of people previously diagnosed with schizophrenia and the discovery that the glutamate blocking drugs such as phencyclidine and ketamine can mimic the symptoms and cognitive problems associated with the condition, while the dopaminergic part of this illness is suggested by the D2 antagonisms that is a common mechanism of action by all antipsychotic drugs, typical and atypical.

The fact that reduced glutamate function is linked to poor performance on tests requiring frontal lobe and hippocampal function and that glutamate can affect dopamine function, all of which have been implicated in schizophrenia, have suggested an important mediating (and possibly causal) role of glutamate pathways in schizophrenia. Further support of this theory has come from preliminary trials suggesting the efficacy of coagonists at the NMDA receptor complex in reducing some of the positive symptoms of schizophrenia. Note that the specific mechanisms of this are yet to be elucidated, as it involves a complex interplay between

Role of Glutamate in Schizophrenia
Role of Glutamate in Schizophrenia
  • 5-HT1A
  • 5-HT2A
  • 5-HT1B
  • 5-HT2C
  • 5-HT6
  • 5-HT7
  • D2
  • D1
  • the endocannabinoid system
  • including CB2, which regulates glial cell NT release.

Glutaminergic abnormalities may also figure in schizophrenia. Specifically, a deficit in metabotropic glutamate receptors 1 and 5 (the primary post-synaptic receptors) results in a relative excess of the activity of the other 6 presynaptic receptors. In turn, a reduction of cAMP levels in these glutaminergic neurons lowers the activity of the NMDA receptor, a receptor crucial for the phenomena of LTP. This then leads to altered K+, Na+, and Ca2+ levels within the cell. In addition, the protein reelin, a crucial modulator of NMDA function in the hippocampus, is in lowered concentrations in both schizophrenic and psychotic bipolar disorder patients.

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