Up-regulation of calcyon results in locomotor hyperactivity and reduced anxiety in mice

Abstract

Gene linkage and association studies have implicated the region of chromosome 10q containing the calcyon locus with attention deficit hyperactivity disorder (ADHD), bipolar disorder, and schizophrenia susceptibility. In addition, levels of calcyon protein and transcripts are also significantly increased in postmortem tissue from schizophrenic brains. But whether altered calcyon expression might be part of the disease etiology or merely a patho-physiological side effect is not known. To begin to address this issue, we generated a transgenic mouse line (Cal OE ) using the human calcyon cDNA in which calcyon expression is up-regulated in a number of forebrain structures including the hippocampus, prefrontal cortex, striatum, and amygdala. Compared to control littermates, the Cal OE mice display a range of abnormal behaviors including spontaneous hyperactivity, reduced anxiety, and/or impaired restraint (harm avoidance) that would indicate that calcyon up-regulation leads to deficits in control over behavioral output.

Calcyon upregulation in adolescence impairs response inhibition and working memory in adulthood

“…In light of the previously observed reduced anxiety-like behavior in the open-field, light-dark and elevated plus maze tasks 39 , the current results indicates that Cal OE mice exhibit complex deficits in control over behavior. Thus, multiple lines of evidence suggest that high levels of calcyon in forebrain disrupt executive functions 54 .…”

“…CaMKIIα, like endogenous calcyon is primarily expressed in the principle cells of forebrain nuclei 35–38 . Transgenic calcyon shows a similar expression pattern 39 .…”

“…The subjects were αCamKII-tTA (tTA) 34 (gift of Dr. T. Abel, U. Penn) single transgenic and TRE-Cal/tTA (Cal OE ) double transgenic mice bred from matings of tTA and TRE-Cal single transgenic parents, and identified by PCR of genomic DNA isolated from mouse tails 39 . Prior to carrying out the present studies, the TRE-Cal and tTA mice were back-crossed to C57Bl/6 for eight generations.…”

“…The anti-human calcyon antibody (Ab) was affinity purified polyclonal rabbit Ab (1:100) 38 . This antibody does not detect endogenous mouse calcyon 39 . Rabbit polyclonal or murine monoclonal antibodies specific for GluR1 and GluR2/3 were used at 1:50.…”

Calcyon Forms a Novel Ternary Complex with Dopamine D1 Receptor through PSD-95 Protein and Plays a Role in Dopamine Receptor Internalization

“…Recent studies, however, have introduced calcyon as a candidate gene for D 1 DR-related neurophysiological disorders. Calcyon levels were elevated in schizophrenia patients (4,5), whereas calcyon transgenic mice showed reduced anxiety and an impaired working memory (6,7). Calcyon was up-regulated in the rodent model of attention deficit hyperactivity disorder (8), and its gene variations are known to be associated with cocaine dependence (9).…”