A miR-137-Related Biological Pathway of Risk for Schizophrenia Is Associated With Human Brain Emotion Processing.

BACKGROUND: miR-137 is a microRNA involved in brain development, regulating neurogenesis and neuronal maturation. Genome-wide association studies have implicated miR-137 in schizophrenia risk but do not explain its involvement in brain function and underlying biology. Polygenic risk for schizophrenia mediated by miR-137 targets is associated with working memory, although other evidence points to emotion processing. We characterized the functional brain correlates of miR-137 target genes associated with schizophrenia while disentangling previously reported associations of miR-137 targets with working memory and emotion processing. METHODS: Using RNA sequencing data from postmortem prefrontal cortex (N = 522), we identified a coexpression gene set enriched for miR-137 targets and schizophrenia risk genes. We validated the relationship of this set to miR-137 in vitro by manipulating miR-137 expression in neuroblastoma cells. We translated this gene set into polygenic scores of coexpression prediction and associated them with functional magnetic resonance imaging activation in healthy volunteers (n1 = 214; n2 = 136; n3 = 2075; n4 = 1800) and with short-term treatment response in patients with schizophrenia (N = 427). RESULTS: In 4652 human participants, we found that 1) schizophrenia risk genes were coexpressed in a biologically validated set enriched for miR-137 targets; 2) increased expression of miR-137 target risk genes was mediated by low prefrontal miR-137 expression; 3) alleles that predict greater gene set coexpression were associated with greater prefrontal activation during emotion processing in 3 independent healthy cohorts (n1, n2, n3) in interaction with age (n4); and 4) these alleles predicted less improvement in negative symptoms following antipsychotic treatment in patients with schizophrenia. CONCLUSIONS: The functional translation of miR-137 target gene expression linked with schizophrenia involves the neural substrates of emotion processing.

Fxr1 regulates sleep and synaptic homeostasis.

The fragile X autosomal homolog 1 (Fxr1) is regulated by lithium and has been GWAS-associated with schizophrenia and insomnia. Homeostatic regulation of synaptic strength is essential for the maintenance of brain functions and involves both cell-autonomous and system-level processes such as sleep. We examined the contribution of Fxr1 to cell-autonomous homeostatic synaptic scaling and neuronal responses to sleep loss, using a combination of gene overexpression and Crispr/Cas9-mediated somatic knockouts to modulate gene expression. Our findings indicate that Fxr1 is downregulated during both scaling and sleep deprivation via a glycogen synthase kinase 3 beta (GSK3ß)-dependent mechanism. In both conditions, downregulation of Fxr1 is essential for the homeostatic modulation of surface AMPA receptors and synaptic strength. Preventing the downregulation of Fxr1 during sleep deprivation results in altered EEG signatures. Furthermore, sequencing of neuronal translatomes revealed the contribution of Fxr1 to changes induced by sleep deprivation. These findings uncover a role of Fxr1 as a shared signaling hub between cell-autonomous homeostatic plasticity and system-level responses to sleep loss, with potential implications for neuropsychiatric illnesses and treatments.

Mental Illnesses-Associated Fxr1 and Its Negative Regulator Gsk3ß Are Modulators of Anxiety and Glutamatergic Neurotransmission.

Genetic variants of the fragile X mental retardation syndrome-related protein 1 (FXR1) have been associated to mood regulation, schizophrenia, and bipolar disorders. Nonetheless, genetic association does not indicate a functional link of a given gene to neuronal activity and associated behaviors. In addition, interaction between multiple genes is often needed to sculpt complex traits such as behavior. Thus, modulation of neuronal functions by a given gene product, such as Fxr1, has to be thoroughly studied in the context of its interactions with other gene products. Glycogen synthase kinase-3 beta (GSK3ß) is a shared target of several psychoactive drugs. In addition, interaction between functional polymorphisms of GSK3b and FXR1 has been implicated in mood regulation in healthy subjects and bipolar patients. However, the mechanistic underpinnings of this interaction remain unknown. We used somatic CRISPR/Cas9 mediated knockout and overexpression to investigate the impact of Fxr1 and its regulator Gsk3ß on neuronal functions directly in the adult mouse brain. Suppression of Gsk3ß or increase of Fxr1 expression in medial prefrontal cortex neurons leads to anxiolytic-like responses associated with a decrease in AMPA mediated excitatory postsynaptic currents. Furthermore, Fxr1 and Gsk3ß modulate glutamatergic neurotransmission via regulation of AMPA receptor subunits GluA1 and GluA2 as well as vesicular glutamate transporter VGlut1. These results underscore a potential mechanism underlying the action of Fxr1 on neuronal activity and behaviors. Association between the Gsk3ß-Fxr1 pathway and glutamatergic signaling also suggests how it may contribute to emotional regulation in response to mood stabilizers, or in illnesses like mood disorders and schizophrenia.

Antipsychotic Drug Responsiveness and Dopamine Receptor Signaling; Old Players and New Prospects.

Antipsychotic drugs targeting dopamine neurotransmission are still the principal mean of therapeutic intervention for schizophrenia. However, about one third of people do not respond to dopaminergic antipsychotics. Genome wide association studies (GWAS), have shown that multiple genetic factors play a role in schizophrenia pathophysiology. Most of these schizophrenia risk variants are not related to dopamine or antipsychotic drugs mechanism of action. Genetic factors have also been implicated in defining response to antipsychotic medication. In contrast to disease risk, variation of genes coding for molecular targets of antipsychotics have been associated with treatment response. Among genes implicated, those involved in dopamine signaling mediated by D2-class dopamine receptor, including DRD2 itself and its molecular effectors, have been implicated as key genetic predictors of response to treatments. Studies have also reported that genetic variation in genes coding for proteins that cross-talk with DRD2 at the molecular level, such as AKT1, GSK3B, Beta-catenin, and PPP2R2B are associated with response to antipsychotics. In this review we discuss the relative contribution to antipsychotic drug responsiveness of candidate genes and GWAS identified genes encoding proteins involved in dopamine responses. We also suggest that in addition of these older players, a deeper investigation of new GWAS identified schizophrenia risk genes such as FXR1 can provide new prospects that are not clearly engaged in dopamine function while being targeted by dopamine-associated signaling molecules. Overall, further examination of genes proximally or distally related to signaling mechanisms engaged by medications and associated with disease risk and/or treatment responsiveness may uncover an interface between genes involved in disease causation with those affecting disease remediation. Such a nexus would provide realistic targets for therapy and further the development of genetically personalized approaches for schizophrenia.