Schizophrenia Research Forum - A Catalyst for Creative Thinking

SfN 2012—Nanosymposium Spans Genes to Experimental Drugs for Psychosis

13 November 2012. The Society for Neuroscience Meeting was held on 13-17 October in New Orleans, Louisiana. On Sunday morning, 14 October, Deanna Smith, of the University of South Carolina in Columbia, moderated a nanosymposium entitled Molecular Genetics and Experimental Therapeutics in Psychotic Disorders.

What's going on at 15q13.3?
Three presentations on a mouse model of 15q13.3 deletion syndrome, which is associated with both schizophrenia and epilepsy, were made by a group of scientists from H. Lundbeck A/S in Copenhagen, Denmark. First up was Jes Lauridsen, who described the generation and characterization of the mouse model. He reported that genes within the deleted region were expressed as expected, at half of normal levels, and that the mice displayed no gross brain abnormalities. However, males exhibited reduced survival and increased body weight, as well as increased stress-induced aggression, similar to what has been reported in human 15q13.3 deletion carriers (Ben-Shachar et al., 2009).

Next, Kim Fejgin focused on the behavioral patterns and seizure susceptibility of the 15q13.3 deletion mice. He described a behavioral phenotype that includes a decreased acoustic startle response (although prepulse inhibition is intact) and impaired long-term spatial reference memory (although short-term memory and working memory are intact), noting that these parallel some aspects of the schizophrenia phenotype. The mice also exhibited a surprising seizure protection phenotype, pointing to a critical role for the 15q13.3 region in modulating excitatory/inhibitory balance.

Jesper Bastlund described the last piece of the 15q13.3 story—the electrophysiological characterization of the mice. A reduced loudness dependence of auditory-evoked potentials (LDAEP) was observed, similar to what has been reported in schizophrenia (Gudlowski et al., 2009). In addition, the mice displayed a general reduction in the auditory-evoked potential, but no change in sensory gating, as well as selective deficits in evoked γ oscillations. Thus, the Lundbeck researchers argue, these mice display pre-attentive processing deficits and electroencephalography (EEG) phenotypes that are observed in schizophrenia.

From genes to drugs
Also from Lundbeck, Ib Klewe described efforts to determine the effects of schizophrenia risk genes in disease-relevant primary neuronal culture assays. Klewe and colleagues performed copy number variant (CNV) gene knockdown using small hairpin RNAs (shRNAs) and then measured NMDA receptor function and parvalbumin immunoreactivity. Although off-target effects reduced the power of the screens, Klewe and colleagues identified two putative genetic regulators of NMDA receptor function and parvalbumin immunoreactivity—KDCT13 and UFD1L—that warrant follow-up with further experiments.

Next up was moderator Deanna Smith, who discussed the mammalian brain development gene Lis1. Smith described the use of rat dorsal root ganglion neuronal cultures to demonstrate that LIS1 and its binding partner NDEL1 regulate microtubule motor protein dynein-dependent axonal transport (Pandey and Smith, 2011). Interestingly, all three proteins interact with the schizophrenia gene DISC1 (see SRF related news story; SRF news story). In ongoing studies, Smith and colleagues are characterizing the lethality observed in mice in which LIS1 is eliminated in adult tissues.

Francoise Gastambide, of Eli Lilly and Company in Surrey, U.K., discussed the effects of LSN2463359, a metabotropic glutamate receptor 5 (mGluR5) positive allosteric modulator, on behavioral deficits induced by exposure to different classes of NMDA receptor antagonists. The drug was effective at normalizing deficits in lever pressing and reversal learning induced by NMDA antagonists, but only those induced by drugs acting outside the ion channel of the receptor (Gastambide et al., 2013).

The final speaker of the nanosymposium was Greet Vanhoof, of Janssen Research and Development in Beerse, Belgium, who presented his work demonstrating that phosphodiesterase 10A (PDE10) inhibitors are dopamine modulators. PDE10 is highly expressed in the medium spiny neurons that make up the indirect and direct dopamine pathways that provide the main inhibitory input to the basal ganglia. Vanhoof showed that PDE10 inhibitors facilitate dopamine D1-mediated neurotransmission while also decreasing D2-mediated neurotransmission, thereby acting as both D1 agonists and D2 antagonists. This dual activity in reducing both hyperactivity and hypoactivity states may extend the therapeutic potential of the PDE10 inhibitors.—Allison A. Curley.