unc5c haploinsufficient phenotype: striking similarities with the dcc haploinsufficiency model

Abstract

DCC and UNC5 homologs (UNC5H) are guidance cue receptors highly expressed by mesocorticolimbic dopamine neurons. We have shown that dcc heterozygous mice exhibit increased dopamine, but not norepinephrine, innervation and function in medial prefrontal cortex. Concomitantly, dcc heterozygotes show blunted mesolimbic dopamine release and behavioral responses to stimulant drugs. These changes appear only in adulthood. Recently, we found an adolescent emergence of UNC5H expression by dopamine neurons and co-expression of DCC and UNC5H by single dopamine cells. Here, we demonstrate selective expression of unc5 homolog c mRNA by dopamine neurons in adulthood. We show that unc5c haploinsufficiency results in diminished amphetamine-induced locomotion in male and female mice. This phenotype is identical to that produced by dcc haploinsufficiency and is observed after adolescence. Notably, and similar to dcc haploinsufficiency, unc5c haploinsufficiency leads to dramatic increases in tyrosine hydroxylase expression in the medial prefrontal cortex, but not in the nucleus accumbens. In contrast, medial prefrontal cortex dopamine-β-hydroxylase expression is not altered. We confirmed that UNC5C protein is reduced in the ventral tegmental area of unc5c heterozygous mice, but that DCC expression in this region remains unchanged. UNC5C receptors may also play a role in dopamine function and influence sensitivity to behavioral effects of stimulant drugs of abuse, at least upon first exposure. The striking similarities between the dcc and the unc5c haploinsufficient phenotypes raise the possibility that functions mediated by DCC/UNC5C complexes may be at play.

Resilience to amphetamine in mouse models of netrin-1 haploinsufficiency: role of mesocortical dopamine

“…In agreement with our previous report showing increased mPFC expression of tyrosine hydroxylase, but not dopamine betahydroxylase (Auger et al 2013), unc5c haploinsufficient mice with sham lesions exhibited significantly greater dopamine concentrations than wild-type sham controls ( Fig. 2e; oneway ANOVA, main effect of condition: F (2,15) =10.10, p= 0.0017).…”

“…We next aimed to determine whether blunted responses to AMPH in netrin-1 haploinsufficient mice emerge only after adolescence, as it is the case for dcc and unc5c deficient mice (Auger et al 2013;Grant et al 2009). We found no differences in locomotor activity between netrin-1 haploinsufficient and wild-type littermates during habituation or following an i.p.…”

“…unc5c haploinsufficient mice Mice heterozygous for a null mutation in the unc5c gene (B6.cgunc5c rcmTg(Ucp)1.23Kz/Slac ) were originally obtained from Dr. S. Ackerman (The Jackson Laboratory, Bar Harbor, ME, USA; Ackerman et al 1997) and maintained as previously described (Auger et al 2013).…”

“…in a volume of 4 ml/kg. Here, we decided to use 2.5 mg/kg AMPH because we have consistently found that it induces blunted AMPH-induced locomotion in our models of reduced netrin-1 receptor signaling (Grant et al 2007;Manitt et al 2013;Auger et al 2013). We have also demonstrated that this dose induces blunted dopamine release in the nucleus accumbens (Grant et al 2007).…”

“…We have hypothesized that DCC receptors act in concert with UNC5C receptors to organize adolescent mPFC dopamine connectivity. Similar to mice that develop with compromised dcc function, adult, but not adolescent, unc5c haploinsufficient mice have increased dopamine innervation to the mPFC and blunted behavioral responses to amphetamine (Auger et al 2013). Thus, the second goal of this study was to address whether selective mPFC dopamine depletion also affects the resilient phenotype exhibited by unc5c haploinsufficient mice.…”