Schizophrenia pathway

Schizophrenia (SCZ) is a severe psychiatric disorder that impacts millions of people globally. It is a complex polygenic condition characterized by positive symptoms (such as hallucinations and delusions), negative symptoms (such as social withdrawal and lack of motivation), and cognitive impairments. There are no distinctive structural or histopathological abnormalities in the brain, and evident biomarkers for the disease are absent. As a result, the molecular and neurobiological mechanisms underlying SCZ remain elusive.

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More than 60 years ago, pharmacological treatments for SCZ emerged, transforming the approach to this complex mental health condition. Since then, these treatments have acted as full or partial antagonists of dopamine D2 receptors. For decades, based on the dopamine hypothesis, this led to the belief that the main underlying cause of the clinical symptoms was a defect in the dopaminergic system. However, only a small percentage of patients achieve full recovery or remission with the currently available medications, and negative and cognitive symptoms are often resistant to existing antipsychotic treatments. Increasing evidence suggests that, in addition to dopaminergic deficiencies, abnormalities in glutamatergic, GABAergic, and serotonergic signaling, as well as inflammation and oxidative stress, also contribute to the pathophysiology of schizophrenia¹.

Researchers have studied gene expression changes in the postmortem brains of individuals with SCZ for many years. Typically, postmortem gene expression studies are conducted on dozens of brains, whereas genome-wide association studies (GWAS) involve thousands of patient samples. So far, GWAS has identified several genetic factors that increase the risk of developing schizophrenia. Two distinct but interconnected mechanisms are at play: common alleles contribute small, cumulative risks to the disorder via single nucleotide polymorphisms (SNPs), while low-frequency, significant effect structural chromosomal abnormalities, known as copy number variants (CNVs), also play a role. Common SNPs with relatively small effect sizes only partially account for the substantial heritability of SCZ, making it particularly challenging to identify copy number variations that are directly causal to the disease. Conversely, gene expression studies in postmortem tissues reveal much stronger disease-associated signals. Even with small sample sizes, consistent gene expression disturbances have been documented in a significant subpopulation of individuals with schizophrenia².

Evidence indicates that targeting metabotropic glutamate (mGlu) receptors could enable more precise regulation of glutamatergic neurotransmission in crucial brain circuits associated with SCZ. Metabotropic glutamate receptors are G protein-coupled receptors classified into three groups based on amino acid sequence homology, G protein binding, pharmacological profile, and signaling. In preclinical studies, the mGlu5 receptor-positive allosteric modulators (PAMs) show efficacy in animal models relevant to all symptom domains in schizophrenia³. The N-methyl-D-aspartate (NMDA) receptor also plays a role in SCZ. NMDA is a glutamate receptor involved in synaptic plasticity and cortical maturation. Multiple studies indicate that NMDA receptor hypofunction at the postsynaptic membrane of glutamate synapses is causally linked to the cellular phenotypes observed in SCZ. NMDA receptor signaling via intracellular signal transduction pathways, such as the AKT‐GSK3β signaling pathway, is modulated by several high-risk SCZ genes, including Disrupted in Schizophrenia 1 (DISC1) and Neuregulin 1 (NRG1). In addition, altered methylation in NMDA receptor subunit genes GRIN2A and 2B has been identified in SCZ.

Furthermore, increasing evidence from human studies suggests a connection between changes in the 14-3-3 protein family and SCZ. The 14-3-3 family consists of multifunctional proteins involved in several key processes, including neurogenesis, neuronal migration, neuronal differentiation, synaptogenesis, and dopamine synthesis. These proteins act as adaptors, influencing various cellular and physiological processes important in developing and progressing neurological disorders. Studies have demonstrated that 14-3-3 proteins are linked with the dopaminergic, glutamatergic, and neurodevelopmental hypotheses of schizophrenia⁴.

SCZ is a multifaceted mental health condition that deeply affects many lives. The heterogeneity of the condition makes it challenging to understand its neurobiological basis. Our schizophrenia pathway poster showcases key proteins and genes linked to the disorder elucidated so far, and ongoing research is helping to clarify potential new targets and mechanisms.

References

1. Tiihonen, J. et al. Molecular signaling pathways underlying schizophrenia. Schizophr. Res. 232, 33–41 (2021).

2. Horváth, S. & Mirnics, K. Schizophrenia as a disorder of molecular pathways.  Biol. Psychiatry  77, 22–28 (2015).

3. Dogra, S. & Conn, P. J. Metabotropic Glutamate Receptors As Emerging Targets for the Treatment of Schizophrenia.  Mol. Pharmacol.  101, 275–285 (2022).

4. Navarrete, M. & Zhou, Y. The 14-3-3 Protein Family and Schizophrenia.  Front. Mol. Neurosci.  15, 857495 (2022).