Post-pubertal emergence of a dopamine phenotype in netrin-1 receptor-deficient mice.
During the pubertal period the mesocortical dopamine (DA) system undergoes substantial reorganization of neuronal connectivity and functional refinement. Netrins are guidance cues involved in the organization of neuronal circuitry. We have previously shown that adult mice that develop with reduced levels of the netrin-1 receptor [deleted in colorectal cancer (DCC)] display selective reorganization of mesocortical DA circuitry, show enhanced mesocortical DA function and exhibit a behavioural phenotype opposite to that observed in animal models of schizophrenia. Here we assess whether the dcc behavioural and DA phenotypes are present prior to the maturation of the mesocortical DA system by comparing dcc-heterozygous and wild-type mice at the post-weaning and peri-pubertal periods on various indices of DA function. At both the post-weaning and peri-pubertal ages, but unlike in adulthood, dcc-heterozygous and wild-type mice show no differences in the number of midbrain DA neurones or in tyrosine hydroxylase protein levels in the medial prefrontal cortex. Furthermore, the elevated baseline concentration of mesocortical DA and DA metabolites observed in adult dcc-heterozygous mice is not present in either post-weanling or peri-pubertal mice. Interestingly, post-weanling, but not peri-pubertal, dcc-heterozygous mice show greater baseline concentrations of DA metabolites in the nucleus accumbens, opposite to what was observed in adulthood. Finally, neither post-weanling nor peri-pubertal dcc-heterozygous mice demonstrate the blunted amphetamine-induced locomotor response observed in adulthood. Thus, these findings show that the 'protective' dcc phenotype has a post-pubertal emergence and indicate that DCC may play a role in the normal maturation of the mesocorticolimbic DA system.
Departments of Psychiatry and Neurology and Neurosurgery, McGill University, Douglas Mental Health University Institute, Montreal, Quebec, Canada.
Alanna
A
Grant
Zoe
Z
Speed
Cassandre
C
Labelle-Dumais
Cecilia
C
Flores
D000375:Aging / Q000502:physiology*; D000661:Amphetamine / Q000494:pharmacology; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects / Q000502:physiology*; D001921:Brain / Q000187:drug effects / Q000254:growth & development / Q000502:physiology*; D000697:Central Nervous System Stimulants / Q000494:pharmacology; D000075389:DCC Receptor; D004298:Dopamine / Q000378:metabolism*; D005260:Female; D008124:Locomotion / Q000187:drug effects / Q000502:physiology; D008297:Male; D008636:Mesencephalon / Q000187:drug effects / Q000254:growth & development / Q000502:physiology; D051379:Mice; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D009474:Neurons / Q000187:drug effects / Q000502:physiology; D009714:Nucleus Accumbens / Q000187:drug effects / Q000254:growth & development / Q000502:physiology; D010641:Phenotype; D017397:Prefrontal Cortex / Q000187:drug effects / Q000254:growth & development / Q000502:physiology; D011956:Receptors, Cell Surface / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D012741:Sexual Maturation / Q000502:physiology*; D025521:Tumor Suppressor Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
D000697:Central Nervous System Stimulants; D000075389:DCC Receptor; C501910:Dcc protein, mouse; D011956:Receptors, Cell Surface; D025521:Tumor Suppressor Proteins; D000661:Amphetamine; D014446:Tyrosine 3-Monooxygenase; D004298:Dopamine