See Allison Curley's snapshots from the conference.
December 3, 2013. The morning of Monday, November 11, brought one of the few 2013 Society for Neuroscience meeting symposia dedicated to schizophrenia. Chaired by Akira Sawa, the session contained many flavors of schizophrenia research, including postmortem molecular studies, findings using a variety of neuroimaging techniques, and analyses of cultured skin cells derived from patients.
The first speaker was Vaidy Swaminathan of the University of Melbourne, Australia, who examined epidermal growth factor receptor (EGFR) mRNA and protein levels in the dorsolateral prefrontal cortex (DLPFC) of subjects with schizophrenia and controls. Although he did not find a change in EGFR mRNA, protein levels were significantly increased in cases. Further examination of the protein data revealed that EGFR protein levels were significantly higher in schizophrenia subjects who did not have a history of suicide attempts than in controls or in patients with a history of suicidal behavior. The group has previously demonstrated that clozapine, but not other antipsychotics, augments EGFR signaling (Pereira et al., 2012). Given that clozapine reduces suicidality in schizophrenia, the current findings suggest that EGFR signaling may underlie this effect, said Swaminathan.
Gianluca Ursini from the Lieber Institute for Brain Development in Baltimore, Maryland, discussed his work on brain-derived neurotrophic factor (BDNF), a protein that has previously been implicated in schizophrenia through genetic and postmortem findings in patients as well as data from animal models (see SRF related conference story). Using RNA sequencing, Ursini screened for variants of BDNF mRNA in the DLPFC of a large sample of schizophrenia subjects and controls. He uncovered several novel splicing events involving a truncated version of BDNF’s exon 1 and reported that expression of these transcripts was higher in schizophrenia cases. In addition, an imaging study demonstrated that a single nucleotide polymorphism that controls the expression of the novel transcripts predicted prefrontal activity in both schizophrenia subjects and siblings. Taken together, the findings provide further evidence for a role for BDNF in the illness.
Using RNA sequencing, Sarven Sabunciyan from Johns Hopkins University, also in Baltimore, examined the expression of repeat elements—stretches of DNA that are repeated in large numbers throughout the genome—in the orbitofrontal cortex of people with schizophrenia, bipolar disorder, and depression. He reported that repetitive element loci were abundantly transcribed in the healthy brain and differentially expressed in a combined group of subjects with schizophrenia or bipolar disorder. Sabunciyan and colleagues hypothesize that some repeat elements are being incorporated into transcripts as splice variants (a process recently described as "exonization"), and that this process is disrupted in neuropsychiatric disorders.
Chang-Gyu Hahn from the University of Pennsylvania in Philadelphia took aim at the NMDA receptor hypothesis of schizophrenia (see SRF Current Hypotheses by Bita Moghaddam and Daniel Javitt, and SRF related news story). Hahn and colleagues examined DLPFC tissue from matched pairs of schizophrenia subjects and controls and found that NMDA receptor complexes are increased in the postsynaptic densities of schizophrenia patients, but the cascade of post-receptor kinases is decreased. The activity of Src kinase, which phosphorylates the NR2 subunits of the NMDA receptor, was decreased in schizophrenia cases, as was Src’s binding capacity for its activators, leading the researchers to hypothesize that attenuation of Src activity is a pathogenic mechanism for NMDA receptor hypofunction in the illness.
Sotiris Posporelis from Johns Hopkins described a preliminary study examining the relationship between brain temperature and cognitive function in six recent-onset schizophrenia subjects and six healthy controls. Temperature in the anterior cingulate, measured using proton magnetic spectroscopy, was significantly correlated with verbal memory performance and negative symptoms. In addition, Posporelis reported that brain temperature was significantly different from core temperature in subjects with schizophrenia, but the two did not differ in control subjects. Brain temperature reflects brain metabolism, so the findings suggest a role for neuroinflammation and oxidative stress (which can alter metabolism) in the illness.
In the lone non-schizophrenia talk of the symposium, Robert Innis from the National Institute of Mental Health, Bethesda, Maryland, described work investigating a downregulation of the cyclic adenosine monophosphate (cAMP) cascade in major depression. The researchers used the radioligand (R)-11C-rolipram, an inhibitor of the phosphodiesterase PDE4 (a component of the cAMP cascade) to approximate cAMP function using positron emission tomography (PET). Consistent with the researchers’ hypothesis, rolipram binding was lower in unmedicated patients with MDD, indicating a downregulation of the cAMP cascade (Fujita et al., 2012). In preliminary results from an ongoing study, antidepressant treatment normalized rolipram binding, suggesting that PDE4 inhibitors could potentially be used to treat major depression (although increased rolipram binding was not associated with symptom improvement).
Next up was Guusje Collin of University Medical Center Utrecht in the Netherlands, who examined the connectivity of the “rich club”—a central collection of strongly interconnected hubs crucial for information integration—in the unaffected siblings of people with schizophrenia by using diffusion tensor imaging. Collin reported that the connections spanning the rich club are impaired in patients with schizophrenia (see SRF related news story), and that rich club connectivity in healthy siblings is intermediate between cases and controls. These findings suggest that impaired rich club connectivity in schizophrenia is genetic in origin.
Hengyi Cao of the University of Heidelberg in Mannheim, Germany, described work designed to clarify the contrasting findings of amygdala dysfunction during emotional processing in unaffected relatives of individuals with schizophrenia. In the current study, Cao and colleagues administered an emotional face-matching task to 160 healthy subjects (60 with a first-degree relative with schizophrenia and 100 without a family history of the illness) undergoing fMRI. Cao reported that there were no alterations in amygdala activation in either group (replicating the findings of a previous study using the same task), suggesting that amygdala activation is unlikely to be an emotion-related intermediate phenotype for schizophrenia. However, decreased connectivity in a limbic subnetwork was observed in the relatives of patients with schizophrenia, he said, pointing to a possible intermediate phenotype for the illness.
Toby Winton-Brown of the Institute of Psychiatry in London, United Kingdom, discussed his work examining salience processing—the way the brain distinguishes important stimuli from the myriad of sensory inputs it receives—which is thought to be disturbed in schizophrenia. Winton-Brown and colleagues developed a novel fMRI task to measure the brain’s response to the novelty, emotion, and monetary values of pictures and found that unmedicated subjects at high risk for developing psychosis showed elevated brain activation to the reward aspects of salience, as well as to images that combined reward and emotion. In addition, the researchers quantified dopamine levels using PET in order to test the predictions made by the methylazoxymethanol acetate (MAM) model of schizophrenia (see SRF related conference story) and found support for the hypothesis that overdrive of the ventral hippocampus results in elevated striatal dopamine in psychosis.
The t(1;11) balanced chromosomal translocation is strongly associated with psychiatric illnesses (see SRF related news story). Two of the affected genes, disrupted-in-schizophrenia (DISC1) and Boymaw, blend together as a consequence of the translocation, forming a DISC1-Boymaw fusion protein, said Kerin Higa of the University of California, San Diego (see SRF related conference story). She reported that expression of the fusion protein in vitro reduces intracellular oxidoreductase activity as well as ribosomal RNA synthesis. Mice with the human DISC1-Boymaw genes knocked in also showed these changes, as well as alterations reminiscent of mental illness such as decreased expression of GAD67, NMDAR1, and PSD95 proteins and several depressive-like behaviors. These results are consistent with the hypothesis that expression of the fusion protein in psychiatric illness may alter the expression of genes involved in GABA and glutamate neurotransmission through a reduction in ribosomal RNA synthesis, said Higa.
Margot Fournier of Lausanne University Hospital in Switzerland described her data suggesting a metabolic signature of reactivity to oxidative stress in early psychosis (see SRF related news story). Fournier and colleagues cultured skin-derived fibroblasts from individuals with early psychosis and performed metabolomic profiling after exposing the cells to oxidative stress. Compared to cells from controls, those from early psychosis patients exhibited alterations in extracellular matrix and collagen metabolism and arginine metabolism pathways that are known to regulate neuronal plasticity and activity. The findings suggest that intermediates of these pathways may represent useful biomarkers in the early phases of schizophrenia, Fournier concluded.
Prior work has suggested that plasma levels of the amino acid homocysteine are elevated in individuals with schizophrenia, said Akira Nishi of the University of Tokushima Graduate School in Japan, but the impacts of gender and genotype have not been conclusively established. Nishi and colleagues measured plasma homocysteine levels in patients with schizophrenia and controls and found that homocysteine levels were higher in schizophrenia subjects than in controls, higher in males than in females, and higher in some alleles of MTHFR, a schizophrenia risk gene involved in the metabolism of homocysteine (see SRF related news story).—Allison A. Curley.