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Neural Circuits of Schizophrenia


Video Transcript

Speaker: Neural circuits of schizophrenia. Schizophrenia is a severe and debilitating psychiatric syndrome, characterized by a complex and heterogeneous symptomatology which can be grouped into positive, negative, and cognitive symptoms. According to the classical dopamine hypothesis of schizophrenia, positive symptoms such as hallucinations and delusions can be attributed to hyperactivation of the dopaminergic mesolimbic pathway. While hypofunctionality of the dopaminergic mesocortical pathway results in negative symptoms such as social withdrawal and blunted affect and cognitive deficits, including impaired memory and attention.

More recent findings implicate other neuronal networks in the pathophysiology of schizophrenia, such as the serotonergic and glutamatergic circuits. In particular, NMDA glutamate receptor hypoactivity at GABAergic interneurons in the prefrontal cortex and serotonin hyperactivity at receptors 5-HT2A receptors and glutamate neurons in the cerebral cortex could be responsible for downstream dopaminergic system alterations leading to positive symptoms. Glutamatergic hypoactivity in the midbrain can lead to altered dopaminergic activity and serotonin hyperactivity within the anterior singulate cortex, and dorsolateral prefrontal cortex can give rise to negative and cognitive symptoms.

Antipsychotics represent the pharmacological standard of care and act on dysregulated dopamine signaling mainly by targeting post synaptic dopamine D2 receptors and attenuating D2 signaling along the mesolimbic pathway, thereby reducing positive symptoms. However, blocking D2 receptors globally throughout the brain can lead to consequences related to other dopamine pathways such as the nigrostriatal pathway, which can lead to adverse effects known as extrapyramidal symptoms or EPS.

Second-generation or atypical antipsychotics reduce such side effects by simultaneously blocking D2 and 5-HT2A receptors. However, many atypical antipsychotics remain associated with EPS and are frequently linked with increased weight gain and metabolic burden related to D2 and 5-HT2A blockade. Furthermore, dopamine inhibition and the dopaminergic tuberoinfundibular pathway increases prolactin secretion from the pituitary gland causing hyperprolactinemia.

Treatments that rely on dopamine receptor blockade have limited effects on ameliorating negative and cognitive symptoms as baseline dopamine activity in the mesocortical pathway is already reduced in schizophrenia, and deficits in serotonin and glutamate circuits are not targeted. A novel therapeutic approach is needed to target the entire spectrum of symptoms of schizophrenia by restoring the baseline activity of neural circuits while avoiding downstream consequences of receptor blockade.

[00:03:24] [END OF AUDIO]

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