Dopaminergic modulation of synaptic transmission in cortex and striatum

Abstract

Among the many neuromodulators used by the mammalian brain to regulate circuit function and plasticity, dopamine (DA) stands out as one of the most behaviorally powerful. Perturbations of DA signaling are implicated in the pathogenesis or exploited in the treatment of many neuropsychiatric diseases, including Parkinson's disease (PD), addiction, schizophrenia, obsessive compulsive disorder, and Tourette's syndrome. Although the precise mechanisms employed by DA to exert its control over behavior are not fully understood, DA is known to regulate many electrical and biochemical aspects of neuronal function including excitability, synaptic transmission, integration and plasticity, protein trafficking, and gene transcription. In this Review, we discuss the actions of DA on ionic and synaptic signaling in neurons of the prefrontal cortex and striatum, brain areas in which dopaminergic dysfunction is thought to be central to disease.

Figure 1. Potential sites of modulation of synaptic transmission by DA

DA may affect P_release by modulating axon terminal excitability (a), Ca²⁺ influx (b) or vesicular release machinery (c). This can occur directly, through activation of presynaptic DA receptors, or indirectly, following the recruitment of postsynaptic DA receptors and liberation of retrograde signaling molecules (d). Postsynaptic DA receptors may influence neurotransmitter detection by modulating the membrane insertion (e), synaptic recruitment (f) or properties (g) of neurotransmitter receptors. In addition, DA alters synaptic integration and the excitability of pre- and postsynaptic membranes by modulating ion channels that control resting potential, Ca²⁺ influx, and action potential threshold and waveform (h).

Figure 2. Intracellular DA signaling pathways

Schematic of cAMP/PKA-dependent (A) and independent (B) pathways recruited by DA receptors. D1- and D2-like receptors are depicted in the same cell for illustrative purposes. Note that some of the targets of Gβγ are ion channels (K_ir3, Ca_V1 and Ca_V2.2). Black and red arrows depict activation and inhibition, respectively. IP₃, inositol triphosphate; DAG, diacylglycerol.

Figure 3. DA modulation of neurotransmitter release

Summary of modulatory effects of DA on transmitter release (small circled arrows) in striatum (A) and cortex (B). Principal cells are depicted in blue, interneurons in green. Glutamatergic, GABAergic and cholinergic synaptic inputs are represented as triangles, circles and squares shaded to reflect modulation by D1- (black) or D2-class receptors (white). Lack of presynaptic modulation by DA shown in gray. The identity of the presynaptic cell (inferred or deducted from paired recordings) is indicated where possible. Note that some modulatory changes only apply to striatal subdivisions (dorsal vs. ventral) and that inconsistencies exist (e.g. DA modulation of GABAergic inputs onto L5 PCs). CIN, cholinergic interneuron; PC, pyramidal cell.