title: 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.
authors.affiliation: Department of Psychiatry and of Neurology and Neurosurgery, McGill University, Douglas Mental Health University Institute, 6875 LaSalle Boulevard, Verdun, QC, Canada, H4H 1R3.
authors.forename: Meagan L
authors.initials: ML
authors.lastname: Auger
authors.forename: Ewoud R E
authors.initials: ER
authors.lastname: Schmidt
authors.forename: Colleen
authors.initials: C
authors.lastname: Manitt
authors.forename: Greg
authors.initials: G
authors.lastname: Dal-Bo
authors.forename: R Jeroen
authors.initials: RJ
authors.lastname: Pasterkamp
authors.forename: Cecilia
authors.initials: C
authors.lastname: Flores
mesh_terms: D000661:Amphetamine / Q000494:pharmacology; D000818:Animals; D000075389:DCC Receptor; D059290:Dopaminergic Neurons / Q000378:metabolism*; D005260:Female; D057895:Haploinsufficiency; D008124:Locomotion / Q000187:drug effects / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008957:Models, Genetic; D000075386:Netrin Receptors; D011956:Receptors, Cell Surface / Q000235:genetics; D017475:Receptors, Nerve Growth Factor / Q000235:genetics* / Q000378:metabolism / Q000502:physiology; D025521:Tumor Suppressor Proteins / Q000235:genetics; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism; D017557:Ventral Tegmental Area / Q000254:growth & development / Q000378:metabolism
chemical_list: D000075389:DCC Receptor; C501910:Dcc protein, mouse; D000075386:Netrin Receptors; D011956:Receptors, Cell Surface; D017475:Receptors, Nerve Growth Factor; D025521:Tumor Suppressor Proteins; C105653:Unc5c protein, mouse; D000661:Amphetamine; D014446:Tyrosine 3-Monooxygenase
keywords: DCC; adolescence; axon guidance; dopamine; mice; schizophrenia