Mesocortical Dopamine Phenotypes in Mice Lacking the Sonic Hedgehog Receptor Cdon
Material below summarizes the article Mesocortical Dopamine Phenotypes in Mice Lacking the Sonic Hedgehog Receptor Cdon, published on June 29, 2016, in eNeuro and authored by Michael Verwey, Alanna Grant, Nicholas Meti, Lauren Adye-White, Angelica Torres-Berrío, Veronique Rioux, Martin Lévesque, Frederic Charron, and Cecilia Flores.
Sonic Hedgehog (Shh) signaling contributes to the specification of midbrain dopamine neurons, which go on to form the ventral tegmental area (VTA) and substantia nigra pars compacta (SNc). Dopamine release from these dopamine projections is involved in diverse behavioral and cognitive processes, which have implications for motor function, addiction, and other psychopathologies. Identifying how the development of these different projections is encoded will help describe the trajectories that lead to healthy or unhealthy phenotypes that depend on this neural circuitry.
In our study, we described how Cdon (cell adhesion molecule-related/downregulated by oncogenes), a co-receptor of Shh, is critically involved in the development of dopamine neurons in the VTA, and specifically those that project to the medial prefrontal cortex (mPFC). Adult Cdon-/- mice had an increased number of mesocortical dopamine neurons and showed reduced behavioral plasticity and sensorimotor gating.
First, we compared Cdon-/- and wildtype (WT) control mice at different developmental times by performing a neuroanatomical quantitative analysis to count the number of mature dopamine neurons expressing tyrosine hydroxylase, an enzyme that is integral to the synthesis and production of dopamine. We found that at embryonic day 12.5, the number of mature dopamine neurons is similar between genotypes.
However, in Cdon-/- embryos, there was an increase in the number of cells expressing a marker of proliferation, suggesting that changes in dopamine cell number could be occurring at later developmental stages. Indeed, by postnatal day zero, Cdon-/- mice showed a pronounced increase in the number of dopamine neurons in the VTA, but not in the SNc, when compared to WT controls. This increase in the number of dopamine neurons in the VTA persisted into adulthood.
Because VTA dopamine neurons are a heterogeneous population and their anatomical and physiological properties are determined by the target they innervate, we next examined whether dopamine and dopamine metabolite content would be altered in the nucleus accumbens (NAcc), mPFC, and/or dorsal striatum (DS), which are three major targets of midbrain dopamine projections.
We found no differences between genotypes in the NAcc and DS. However, dopamine content was significantly increased in the mPFC of adult Cdon-/- mice. This finding suggested that Cdon is specifically involved in the development of mesocortical dopamine projections. This was corroborated when we used unbiased stereology to show that the density of dopamine projections to the cingulate, prelimbic, and infralimbic subregions of the mPFC was significantly greater in Cdon-/- mice versus WT controls.
Finally, we tested Cdon-/- and WT mice on behavioral tasks that are known to depend, at least in part, on mesocortical dopamine circuitry. We found that sensorimotor gating, as measured by pre-pulse inhibition of the acoustic startle response, was reduced in Cdon-/- mice. Furthermore, behavioral plasticity, measured as sensitization to the locomotor activating effects of the stimulant drug of abuse amphetamine upon repeated administration, was also attenuated in Cdon-/- mice.
Taken together, this study helps to establish Cdon as an important part of the developmental organization and function of the mesocortical dopamine pathway. Our study provides novel insights on the role of Cdon and describes changes in VTA dopamine neurons that could have implications for psychopathologies such as schizophrenia and attention deficit hyperactivity disorder.
Mesocortical Dopamine Phenotypes in Mice Lacking the Sonic Hedgehog Receptor Cdon. Michael Verwey, Alanna Grant, Nicholas Meti, Lauren Adye-White, Angelica Torres-Berrío, Veronique Rioux, Martin Lévesque, Frederic Charron, Cecilia Flores. eNeuro Jun 2016 DOI: 10.1523/ENEURO.0009-16.2016