Developmental origins of brain disorders: roles for dopamine

Abstract

Neurotransmitters and neuromodulators, such as dopamine, participate in a wide range of behavioral and cognitive functions in the adult brain, including movement, cognition, and reward. Dopamine-mediated signaling plays a fundamental neurodevelopmental role in forebrain differentiation and circuit formation. These developmental effects, such as modulation of neuronal migration and dendritic growth, occur before synaptogenesis and demonstrate novel roles for dopaminergic signaling beyond neuromodulation at the synapse. Pharmacologic and genetic disruptions demonstrate that these effects are brain region- and receptor subtype-specific. For example, the striatum and frontal cortex exhibit abnormal neuronal structure and function following prenatal disruption of dopamine receptor signaling. Alterations in these processes are implicated in the pathophysiology of neuropsychiatric disorders, and emerging studies of neurodevelopmental disruptions may shed light on the pathophysiology of abnormal neuronal circuitry in neuropsychiatric disorders.

Keywords: D1 receptor; D2 receptor; dendrite; frontal cortex; migration; neurodevelopment; neuropsychiatric disease; striatum.

FIGURE 1

(A) During midgestation DA receptors have subtype-specific effects both on neuronal proliferation and interneuron migration; (B) During late-gestation DA receptors continue to be bioactive and regulate dendritic complexity of both cortical pyramidal neurons and striatal medium spiny projection neurons in a subtype-specific manner; (C) DA receptor expression typically peaks during adolescence and then declines. For D1 receptors in the frontal cortex, this is not just a reduction in total receptors per neuron, but rather a “pruning” of a subpopulation of D1 receptors that are transiently expressed on the terminals of cortico-accumbens neurons (Andersen et al., 2000; Brenhouse et al., 2008); (D) Photomicrographs demonstrate the localization of D1 [red, Drd1-tdTomato reporter (Ade et al., 2011)] and D2 [Drd2-eGFP reporter (Gong et al., 2003)] receptors in the rostral (left) and caudal (right) striatum of the adult mouse. Note the heavy labeling of D1 and D2 expressing cells within the CPu and NAc (note very few of these neurons co-express both receptors). More caudally (right) eGFP-labeled terminals can be visualized within the GP, representing the D2+ indirect pathway. D1+ axons, in contrast, bundle ventromedially to the GP and will eventually terminate in the substantia nigra and ventral tegmental area. CPu, caudate-putamen; Ctx, cortex; GE, ganglionic eminences; GP, globus pallidus, mFC, medial frontal cortex, and NAc, nucleus accumbens. The brain images in panels (B) and (C) are courtesy of the Allen Developing Mouse Brain Atlas and are available from: .

FIGURE 2

Nigrostriatal, mesocortical, and mesolimbic pathways cartooned in an adult mouse brain in the sagittal plane. Substantia nigra pars compacta (SN) projects to GABAergic projection neurons in the dorsal striatum. The ventral tegmental area (VTA) projects to both subcortical limbic areas and to the medial frontal cortex.