Schizophrenia Research Forum - A Catalyst for Creative Thinking

SfN 2012—Olfactory Neurons and Suspect SNPs in Psychotic Disorders

20 November 2012. The Society for Neuroscience Meeting was held on 13-17 October 2012 in New Orleans, Louisiana. On Tuesday morning, 16 October, Amanda Mitchell moderated a nanosymposium entitled Stem Cell and Epigenetic Analyses in Psychotic Disorders.

The nose knows
Several speakers described work with cells obtained from nasal biopsies. Aziza Manceur of Philadelphia’s University of Pennsylvania examined the molecular mechanisms underlying the effects of lithium on the mTOR signaling pathway, specifically the mTOR complex 2 (mTORC2), using neuroepithelium cells. The researchers found that lithium decreased phosphorylation of mTORC2 and Akt, both hallmarks of mTORC2 activity.

Shin-ichi Kano of Johns Hopkins University in Baltimore, Maryland, discussed a molecular profiling approach and functional gene group analysis using olfactory cells derived from schizophrenia patients. The approach suggested that genes in the “phase II detoxification system,” involved in the protection against endogenous stress, are significantly altered in schizophrenia (Kano et al., 2012). Kano then presented data showing that gene expression of one particular enzyme, glutathione S-transferase theta 2 (GSST2), from this system may be more frequently decreased in schizophrenia.

Also of Johns Hopkins, Chi-Ying Lin presented methods for using nasal biopsies and dissociated cell cultures to obtain two kinds of olfactory cells. The first, immature neuronal cells, can be used to detect schizophrenia-associated changes that aren’t detectable in lymphoblastoid cell lines (LCLs), and the second, olfactory sphere-derived cells, can be differentiated into mature cells.

Scrutinizing SNPs
Joshua Hunsberger from the National Institute of Mental Health described work investigating the potential interaction between microRNA (miRNA) mechanisms and single nucleotide polymorphisms (SNPs) associated with the lithium response in bipolar disorder. Using LCLs derived from bipolar patients characterized as lithium responders or non-responders, Hunsberger and colleagues identified lithium-responsive miRNAs and mRNAs, as wells as potential SNP associations with miRNA binding sites.

The next speaker, Amanda Mitchell from the Mt. Sinai School of Medicine in New York City, described work examining whether schizophrenia-associated SNPs interact with functional regions of the genome. To do this, Mitchell and colleagues captured the 3D architecture of chromatin using chromosome conformation capture (3C) in prefrontal cortex, a technique that can be used to look at higher-order chromatin structure. Preliminary experiments suggest that intergenic schizophrenia-associated SNPs do interact with functional regions such as transcription start sites and enhancer regions.

Joseph Callicott of the National Institute of Mental Health discussed the use of a propensity score, a weighting scheme to take into account multiple schizophrenia risk variants simultaneously. The researchers examined multiple SNPs in relationship to the prefrontal cortex inefficiency phenotype of schizophrenia. Using fMRI data during a working memory task from healthy control subjects, the researchers calculated propensity scores for either 19 or 230 putative schizophrenia risk SNPs. Both scores were associated with prefrontal activation, and those with the highest propensity scores (most schizophrenia-like) showed the least prefrontal cortex efficiency, suggesting that propensity scores may be useful for summarizing the collective effects of multiple SNPs.

Stem cells and NT2N cells
Vivian Hook, from the University of California, San Diego, described the use of human induced pluripotent stem cells (hiPSC) obtained from skin biopsies of schizophrenia and control subjects to study changes in secreted neurotransmitters in the illness. She showed data demonstrating that hiPSC neurons secrete the catecholamines dopamine, norepinephrine, and epinephrine, as well as several neuropeptides. The neurons derived from schizophrenia patients show elevated levels of the catecholamines and neuropeptides enkephalin and dynorphin compared to neurons derived from controls. The elevated levels of the catecholamines, but not the neuropeptides, were reversed with the antipsychotic loxapine.

In a departure from the schizophrenia- and bipolar disorder-related talks in the rest of the symposium, the final speaker was Li Cui of the University of Arkansas for Medical Sciences in Little Rock, who discussed the use of transplanted human teratocarcinoma cells differentiated into neurons (NT2N cells) as a potential treatment for epilepsy. To best treat the disorder, cells would need to be inhibitory in nature and controllable to allow activation following detection of a seizure, and thus Cui and colleagues bioengineered NT2N cells to express channelrhodopsin-2, allow optogenetic control and overexpress glutamic acid decarboxylase to increase GABA production. Cui noted that future studies are needed to determine if these cells will survive transplantation and effectively control seizures.—Allison A. Curley.