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SfN 2015—From Mice to Humans in Schizophrenia Neuropathology Session

2 Nov 2015

November 3, 2015. The 2015 Society for Neuroscience (SfN) meeting was held from October 17 to 21 in Chicago, Illinois, attracting nearly 30,000 neuroscientists. Schizophrenia was not as prominently featured as it has been at previous SfN meetings, but there were several sessions devoted to the topic. The first was a symposium on Monday morning that covered quite a wide range of talks under the rubric Neuropathology: Mechanisms and Biomarkers.

The chair of the session, Kim Do of the University of Lausanne in Switzerland, gave an update of her laboratory's long-standing exploration of oxidative stress/redox mechanisms that might underlie schizophrenia (see SRF related news report; SRF related conference report). In the current study, the researchers have narrowed their focus to people at the early stages of psychosis, before adaptive brain changes or treatment effects might appear. Does reported magnetic resonance spectroscopy (MRS) evidence that those patients with a genetic variant that reduces levels of the oxidative species scavenger glutathione in fact have low levels of glutathione in medial prefrontal cortex (mPFC)? She also showed data indicating that mPFC glutathione levels were correlated with blood measures of a ratio of two enzymes that control glutathione levels, suggesting a possible peripheral biomarker for people at high risk of developing schizophrenia.

Joelle Lavoie of Johns Hopkins University in Baltimore, Maryland, reported on work with neural cells derived from the nasal epithelium of people with mental illness, wherein she and colleagues are looking at whether there are differences to be found in the main steps—transcription and translation—of generating proteins from the genetic code. Lavoie reported that there appear to be virtually no differences in overall levels of transcription between cells from people with schizophrenia and those from control subjects, but numerous instances of up- or downregulation of translation. This was not found in bipolar disorder.

Another line of research, presented by Rita Marreiros of Heinrich Heine University in Dusseldorf, Germany, looks for insoluble proteins in mental disorders, on the theory that these could have deleterious effects on biological function, though more subtle than the proteinopathies of neurodegenerative disorders (see SRF related news report). Insoluble forms of NKCC1 protein, which regulate neuronal excitability, especially during early development, were detected in schizophrenia and mood disorder brain samples, but not in controls. In a Northern Finnish birth cohort, the researchers found that NKCC1 genotype was associated with anhedonia in schizophrenia patients.

Melanie Sauer of Macquarie University in Sydney, Australia, presented data that merge two lines of research: explorations of the role of ventral hippocampus in mediating some of the symptoms of schizophrenia and the use of amphetamine to model psychosis. Sauer and colleagues measured gene expression in the ventral hippocampus of rats exposed to methamphetamine and found significant changes in up- and downregulation of hundreds of genes relative to control animals. In her discussion, she focused on some of the functional categories that were most prominent, including energy metabolism, oxidative stress, and GABA neurotransmission.

In quite a different paradigm, Jordan Hamm of Columbia University in New York City approached psychosis as a brain state, shared among several psychiatric disorders, including schizophrenia, as well as induced by many things such as drug abuse or sleep deprivation. Working from evidence that perceptions and thoughts reflect recurrent patterns of activated neocortical neurons, he hypothesized that disruptions in these patterns could underlie the abnormal thought and perception of psychosis. As a test of this idea, he administered ketamine to awake mice and used two-photon calcium imaging to observe activity in visual cortex. Hamm found a decrease in population-level "up-states" of activity, which he described as a disorganized pattern of cortical activity. Such a state could underlie positive or cognitive symptoms of psychosis.

Il Hwan Kim of Duke University in Durham, North Carolina, gave a presentation of his research published earlier this year (see SRF related news report) on a mouse model of dendritic spine loss, which recapitulates and ties together some features of schizophrenia and identifies a circuit that appears to be responsible for antipsychotic drug-sensitive locomotor agitation.

An outlier in this neurobiology symposium was Akira Nishi of Tokushima University in Japan, presenting a family-based exome sequencing study. In 18 trios of people with schizophrenia and their two unaffected parents, the researchers found more than 400 single nucleotide substitutions or insertions/deletions of nucleotides. Of these, they validated nine de novo non-synonymous missense mutations in schizophrenia patients. Nishi specifically discussed two that might be of etiologic interest: Mutations in the genes TBL1XR1 and ABCD4 were predicted to be deleterious to protein function.

Not-so-candidate genes

Some of the research presented falls into a sometimes controversial category—follow-up from or connections made to genes that were found to be associated with schizophrenia in the pre-genomewide association study (GWAS) era, and which have not been supported to date in GWAS. The grounds for including this work in psychosis meeting sessions are typically several: that mutations in these genes disturb key cellular processes and lead to behavioral or pathological abnormalities with some homology to psychotic disorders, or that the protein products interact with a GWAS-supported gene (or disrupted in schizophrenia 1 [DISC1]). The hypothesis that there are a multitude of paths to the neuronal dysfunction of psychosis—in addition to many more genes to be fingered by ever larger GWAS—provides underlying justification for continued work on molecules in the quest to find better treatments.

Renata Batista-Brito of Yale University in New Haven, Connecticut, reported that disrupting neuregulin 1 signaling by knocking out the ErbB4 receptor in embryonic mice alters the inhibition-excitation balance of local field potentials in adult mouse visual cortex. Re-expression of the ErbB4 receptors during the critical postnatal visual plasticity period, but not later, rescued the local field potential abnormality. However, the researchers were also able to restore normal local field potential by optogenetically enhancing interneuron activity in the adult mice.

A mouse with a knocked-in version of the human G72-G30 variant on chromosome 13 previously associated with schizophrenia and bipolar disorder shows a loss of parvalbumin-positive neurons and abnormalities of slow-wave sleep, said Anna Papazoglou of the Federal Institute for Drugs and Medical Devices in Bonn, Germany. She found that nicotine treatment normalized the aberrant beta and gamma oscillations in hippocampus that were also detected in this mutant mouse.

Ed Oh of Duke University described research on pericentriolar material 1 (PCM1), whose gene was an early schizophrenia candidate risk gene that interacts with DISC1. Knocking out PCM1 in mice interferes with cytoskeleton construction in cilia, cellular organelles that play varied roles in neurodevelopment and in sensing the extracellular environment. Oh and colleagues found abnormal cilia in areas of the amygdala, hippocampus, and prelimbic cortex. It appeared that these effects were progressive and correlated with increases in behavior abnormalities as mice entered adulthood. However, Oh and colleagues also took their work into humans, finding an enrichment of rare alleles in the PCM locus in people with treatment-resistant schizophrenia.—Hakon Heimer.