Tran Nguyen

Introduction. Schizophrenia is a mental disorder with positive symptoms, such as delusions and hallucinations, and negative symptoms, such as flat affect and social isolation, compromising the core diagnostic criteria.¹ Schizophrenia typically develops in early adulthood; it is rare before 16 years of age.¹ The mental disorder currently affects about 0.3% of the global population.¹ Risk factors include environmental challenges during perinatal development, psychosocial stress, substance use, and genetics associated with the disease.² Currently, there is no known cure for schizophrenia, but there are treatments, such as antipsychotics, that can reduce symptoms to allow affected individuals to live functioning lives.³ Studies have found that metabotropic glutamate receptors (mGluR) are involved in the etiology of schizophrenia especially mGluR₁ and mGluR₅.^{4, 5, 6, 7} Allosteric modulation of the metabotropic glutamate receptors have been found to reduce symptoms of schizophrenia in mice studies.^{5, 6, 7} These findings could suggest a potential selective therapy for schizophrenia. Methods. The schizophrenia mice models were used. Systemic administration of the biased mGluR₅ positive allosteric modulator (PAM) or mGluR₁ negative allosteric modulator (NAM) was conducted. Slices of the prefrontal cortex underwent electrophysiological analysis to collect data on spontaneous inhibitory postsynaptic currents (sIPSCs) and field excitatory postsynaptic potentials (fEPSPs). Statistical analyses were done using ANOVA to compare electrophysiological results. Molecular dynamics stimulations were conducted to study the molecular mechanisms of the PAMs and NAMs of mGluR₅. Results. A mGluR₅ PAM restores NMDA receptor function, restores long term potentiation (LTP), rescues the learning deficits and neurochemical abnormalities, reverses Akt/GS3K/mTOR signaling deficits, and restores the contextual memory impairments in a mice genetic model in schizophrenia.⁵ Coactivation of mGluR₅ and M₁ receptors contributes to muscarinic long term depression (mLTD) by increasing GABA_A-dependent inhibition in the prefrontal cortex (PFC) pyramidal neurons.⁶ mGluR₅ PAMs can reverse deficits in PFC function and cognition.⁶ Activation of mGluR₁ is necessary for M₄-induced reductions in striatal dopamine release.⁷ Activation of mGluR₁ reduces striatal DA release via the activation of CB₂ cannabinoid receptors.⁷ Stimulation of thalamostriatal afferents activates mGluR₁, attenuating striatal DA release.⁷ PAM destabilized the TM3−TM6 ionic lock and induced TM6 outward movements on the intracellular side, characteristic of class A GPCR activation.⁸ Conclusions. Allosteric modulation of mGluR₁ and mGluR₅ in mice genetic models of schizophrenia rescued neuroplasticity deficits and display anti-psychotic like effects. The ways that PAMs rescue neurocognitive deficits include restoring NMDA receptor function, restoring LTP, reverse signaling deficits, contributing to mLTD, and reducing DA release.

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