Dopaminergic signaling in dendritic spines

Abstract

Dopamine regulates movement, motivation, reward, and learning and is implicated in numerous neuropsychiatric and neurological disorders. The action of dopamine is mediated by a family of seven-transmembrane G protein-coupled receptors encoded by at least five dopamine receptor genes (D1, D2, D3, D4, and D5), some of which are major molecular targets for diverse neuropsychiatric medications. Dopamine receptors are present throughout the soma and dendrites of the neuron, but accumulating ultrastructural and biochemical evidence indicates that they are concentrated in dendritic spines, where most of the glutamatergic synapses are established. By modulating local channels, receptors, and signaling modules in spines, this unique population of postsynaptic receptors is strategically positioned to control the excitability and synaptic properties of spines and mediate both the tonic and phasic aspects of dopaminergic signaling with remarkable precision and versatility. The molecular mechanisms that underlie the trafficking, targeting, anchorage, and signaling of dopamine receptors in spines are, however, largely unknown. The present commentary focuses on this important subpopulation of postsynaptic dopamine receptors with emphases on recent molecular, biochemical, pharmacological, ultrastructural, and physiological studies that provide new insights about their regulatory mechanisms and unique roles in dopamine signaling. The Central Dopaminergic Systems: An OverviewDopamine (DA) is a prototypical slow neurotransmitter that plays pivotal roles in a variety of cognitive, motivational, neuroendocrine, and motor functions [1][2]. Two major groups of DAcontaining neurons in the mammalian brain reside in the substantia nigra pars compacta (SN) and the ventral tegmental area (VTA) [3]. SN neurons form the nigrostriatal pathway, which projects mainly to the dorsal part of striatum where they control postural reflexes and initiation of movements. VTA neurons give rise to two pathways: the mesolimbic pathway, which projects to the subcortical and limbic nuclei, and the mesocortical pathway, which projects mainly to the cingulate, entorhinal and medial prefrontal cortices. Dysfunction of dopaminergic transmission in these major pathways has been implicated in an array of neurological and neuropsychiatric disorders, including Parkinson's disease, Huntington's diseases, schizophrenia, attention-deficit hyperactivity disorder (ADHD), and drug addiction [1][2]. Drugs targeting dopaminergic mechanisms are widely used to manage these and other conditions.The action of DA is mediated by a family of seven-transmembrane G protein-coupled receptors (GPCRs) encoded by at least five DA receptor genes (D1, D2, D3, D4, and D5) in the mammalian brain [4]. These receptors are classified into two subfamilies, the D1-class and Corresponding author: Wei-Dong Yao, Ph.D., Department of Psychiatry, Harvard Medical School, Beth Israel Deaconess Medical Center, New England Primate Research Center, One Pine Hill Drive, P.O. Box 9102, Southborough,...

Loss of dendrite stabilization by the Abl-related gene (Arg) kinase regulates behavioral flexibility and sensitivity to cocaine

“…1C). This finding is consistent with age-related spine and basal dendrite regression in arg Ϫ/Ϫ mice (11,19,20).…”

“…Consistent with the regression of basal dendritic arbors and spines in adult arg Ϫ/Ϫ mice, we also found evidence of an exaggerated age-related loss of D1/D2 protein from high expression levels at P21 to lower levels in adulthood in arg Ϫ/Ϫ mice (11,19,20). We would not necessarily expect to detect an overall D2 deficit because neuronal D2 receptors account for only a subset of total PFC D2 expression (32).…”

“…This response pattern recapitulates oPFC lesion effects in the same type of spatial reversal task (20). Moreover, perseverative responding after cocaine in arg Ϫ/Ϫ mice was profoundly enhanced at a dose that left wt mice unaffected.…”

“…1C). This finding is consistent with age-related spine and basal dendrite regression in arg Ϫ/Ϫ mice (11,19,20).Arg Deficiency Impairs Inhibitory Control. Adult arg Ϫ/Ϫ mice were first trained to respond (nose poke) on one of three nose poke recesses in operant conditioning chambers to obtain food rein-…”

Computational models of reinforcement learning: the role of dopamine as a reward signal

“…The influence of dopamine on synaptic plasticity depends on numerous factors including the targeted cell type, the specific receptors activated and the brain region under consideration (Bissière et al 2003;Calabresi et al 2007;Otani et al 2003;Shen et al 2008;Wickens 2009;Yao et al 2008). Reinforcement learning results from the dynamical interaction between numerous brain networks mediating the acquisition of conditioning tasks and action selection.…”