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Neurocan Gene Implicated in Mania

21 September 2012. In a study published in the September issue of the American Journal of Psychiatry, researchers describe an association of glycoprotein gene neurocan (NCAN) with mania in a combined cohort of subjects with schizophrenia, bipolar disorder, and major depressive disorder. Marcella Rietschel and Andreas Zimmer of the Germany’s Manheim University and University of Bonn, respectively, and their colleagues also find that NCAN knockout mice exhibit mania-related phenotypes.

NCAN is a component of the extracellular matrix and is implicated in a variety of cellular events including adhesion, migration, and axonal outgrowth (Järveläinen et al., 2009). It has recently become of interest to psychiatric researchers since genome-wide association studies have linked the rs1064395 allelic variant in NCAN with both schizophrenia and bipolar disorder susceptibility (Mühleisen et al., 2012; Cichon et al., 2011).

In the current study, first authors Xavier Miró and Sandra Meier made genotype-phenotype correlations in over 1,700 subjects with schizophrenia, bipolar disorder, and major depression. The researchers performed a principal component analysis on responses to 69 questions from the Operational Criteria Checklist for Psychotic Illness (OPCRIT), identifying five symptom dimensions: reality distortion, mania, depression, disorganization, and drug abuse/dependence. In the combined cohort of all three illnesses, rs1064395 carriers had significantly higher mania factor scores than non-carriers. No significant differences in any of the dimensions were observed when diagnosis was entered into the model as a cofactor. Specifically, rs1064395 carriers differed from non-carriers in the overactivity sub-dimension of mania, which includes excessive activity, elevated mood, decreased need for sleep, and reckless behavior.

Next, Rietschel and Zimmer turned to NCAN knockout (KO) mice. Consistent with a role for NCAN in mania, NCAN KO mice exhibited several mania-like behaviors. Compared to wild type animals, NCAN KOs were hyperactive, exhibiting increased exploratory behavior in an open field as well as increased locomotor activity in their home cages. In addition, when given a choice between a saccharin solution and an unsweetened substance, they preferred the sweetened liquid more than wild type animals did, a behavior thought to represent a hyperhedonic state that can be associated with mania.

In the forced swim test, a classic measure of behavioral despair, NCAN KO mice spent less time immobile than wild type animals, suggestive of the mania symptom of increased vigor. In addition, in both the elevated plus and elevated zero mazes, the knockout mice spent more time in the open arms than their wild type counterparts, indicating lower levels of anxiety and perhaps modeling the increased risk-taking of mania. Treatment with the mood stabilizer lithium reversed these behaviors, significantly increasing the time the knockouts, but not the wild types, spent immobilized and decreasing the time both genotypes spent in the open arms of the elevated zero maze.

In a marble burying test, the NCAN KO mice buried more marbles than wild type mice, and lithium treatment reduced burying in knockout but not wild type animals. Although classically thought to be a measure of anxiety in which the animal tries to cover novel objects that may be harmful, the authors note that these results may instead reflect a repetitive and perseverative digging behavior that is reminiscent of mania (Thomas et al., 2009). Importantly, since lithium did not reduce overall motor activity in the knockout mice, the excessive burying is unlikely to be the consequence of the hyperactivity also observed in these animals.

Next the researchers measured the animals’ locomotor activity in response to amphetamine treatment. At a low dose of amphetamine (that did not alter the behavior of wild type mice) knockout animals exhibited increased locomotor activity, indicating a hypersensitivity to amphetamine that was abolished after lithium treatment. Finally, similar to patients with schizophrenia and bipolar disorder with mania (Perry et al., 2001), NCAN KO mice displayed decreased sensorimotor gating, as measured by prepulse inhibition of the acoustic startle response.

Taken together, these human and animal data are suggestive of a role for NCAN in the etiology of mania, and suggest that NCAN KO mice are a useful animal model of human mania. Although the exact mechanism(s) by which NCAN elevates mania risk is unclear, its crucial role during development (Cichon et al., 2011) supports the hypothesized neurodevelopmental origins of schizophrenia and bipolar disorder.—Allison A. Curley.

Miró X, Meier S, Dreisow ML, Frank J, Strohmaier J, Breuer R, Schmäl C, Albayram O, Pardo-Olmedilla MT, Mühleisen TW, Degenhardt FA, Mattheisen M, Reinhard I, Bilkei-Gorzo A, Cichon S, Seidenbecher C, Rietschel M, Nöthen MM, Zimmer A. Studies in humans and mice implicate neurocan in the etiology of mania. Am J Psychiatry . 2012 Sep 1 ; 169(9):982-90. Abstract

Comments on News and Primary Papers
Comment by:  Melvin G. McInnis
Submitted 2 October 2012
Posted 2 October 2012

This is a very important paper. The identification of an observed and measured aberrant phenotype in an animal model that is rescued by an intervention commonly used in management of mania represents the standard for biological research in psychiatry. This is extraordinary work by a phenomenal team. The challenge is whether the observed phenotype in the mouse is related to bipolar mania in humans or some other neuro-excitable phenotype.

One cannot but think back to the original experiments of John Cade, where the lithium story began, that demonstrated a calming effect in rodents.

View all comments by Melvin G. McInnis