1 Apr 2015
April 2, 2015. Against a mountainous backdrop, nearly 1,000 schizophrenia researchers delved into the science of the 15th International Congress of Schizophrenia Research (ICOSR) from March 29 to April 1 in Colorado Springs. This year's meeting was a notable one, as Congress founders Carol Tamminga and Chuck Schulz are stepping down from its leadership after almost 30 years at the helm. Tamminga and Schulz were regularly hailed from the podium throughout the meeting for their vision, dedication, and hard work.
In the first plenary talk, on Sunday morning, March 29, Elisabeth Binder of the Max Planck Institute of Psychiatry in Munich shared her explorations of genomic responses to stress. Based on studies that find interactions between the stress of childhood trauma and risk for mental illness, Binder showed that stress induced expression changes in 4,000 genes in humans. A genomewide association study found over 3,000 single nucleotide polymorphisms (SNPs) associated with these genes' expression. Strikingly, the SNPs linked to genetic responses to stress were far from the genes they were regulating—on average half a mega-base pair away—and were enriched in enhancer regions that promote transcription in the brain. Other experiments indicated that long-range interactions were at play, with a loop along a chromosome bringing enhancers in contact with the gene of interest. These stress-related SNPs also overlapped with risk SNPs identified for schizophrenia and major depressive disorder, and this may help explain how trauma acts as a risk factor for psychiatric disorders.
Gallons of glutamate
In a morning symposium, researchers examined evidence for aberrations in glutamate, the brain's key excitatory neurotransmitter, in schizophrenia. Noting evidence of increased glutamate release in the hippocampus of unmedicated people with schizophrenia, as well as increased blood flow there consistent with hyperactivity, Adrienne Lahti of the University of Alabama at Birmingham described recently published work that found lower than normal correlations between hippocampal activity and other parts of the brain, also known as functional connectivity, at rest in unmedicated people with schizophrenia (Kraguljac et al., 2014). Treatment with antipsychotic drugs for six weeks normalized functional connectivity, with stronger connections correlated with a greater decrease in symptoms. A new effective connectivity study, which gets at which region drives activity in another region, pointed to the hippocampus as the source of weakened connectivity (Hutcheson et al., 2015).
Camilo de la Fuente-Sandoval of Instituto Nacional de Neurologia y Neurocirugia in Mexico City followed with a focus on the dorsal caudate, a region that seems to flag imminent psychosis. His previous work had found higher glutamate levels in the dorsal caudate of people experiencing their first episode of psychosis (de la Fuente-Sandoval et al., 2013), and he presented a replication of this finding in a new cohort of antipsychotic-naive people in a first episode of psychosis. He suggested that this may warrant increased effort toward finding glutamate-related therapeutics.
One idea for why glutamate becomes elevated in schizophrenia casts blame on sluggish interneurons. These interneurons can be activated by glutamate via their NMDA receptors, which are thought to be underactive in schizophrenia. In this situation, then, interneurons would fire less and release less inhibitory GABA onto excitatory cells across their synapses. This would then free the excitatory cells from inhibition, resulting in extra firing and extra glutamate release. Lawrence Kegeles of Columbia University in New York City tested this scenario in an experiment that temporarily induced a state of NMDA receptor hypofunction in healthy controls by infusing ketamine, an NMDA receptor blocker. Using proton magnetic resonance spectroscopy to measure biochemical changes in medial prefrontal cortex, he found that glutamate was, as expected, increased by 17 percent relative to controls—but that GABA was also increased by 11 percent. This concomitant increase is consistent with what is found in unmedicated people with schizophrenia (Kegeles et al., 2012). Kegeles surmised that the increased glutamate levels are still consistent with NMDA receptor hypofunction, but that circuitry beyond the mPFC must be invoked to explain the increase in GABA.
James Meador-Woodruff of the University of Alabama at Birmingham departed from brain imaging to describe data from postmortem studies that show irregularities in how glutamate receptors are shuttled around the neuron in schizophrenia. A new project involved developing a way to measure palmitoylation, a post-translational modification that adds fatty acids to a nascent protein, in postmortem brain. Palmitoylation acts as a trafficking signal to direct proteins from the endoplasmic reticulum or Golgi apparatus to the synapse. Meador-Woodruff reported that palmitoylation was down by 30 percent in various glutamate-related synaptic proteins in schizophrenia, which could indicate localization problems.—Michele Solis.