Heterogeneity in Dopamine Neuron Synaptic Actions Across the Striatum and Its Relevance for Schizophrenia

Abstract

Brain imaging has revealed alterations in dopamine uptake, release, and receptor levels in patients with schizophrenia that have been resolved on the scale of striatal subregions. However, the underlying synaptic mechanisms are on a finer scale. Dopamine neuron synaptic actions vary across the striatum, involving variations not only in dopamine release but also in dopamine neuron connectivity, cotransmission, modulation, and activity. Optogenetic studies have revealed that dopamine neurons release dopamine in a synaptic signal mode, and that the neurons also release glutamate and gamma-aminobutyric acid as cotransmitters, with striking regional variation. Fast glutamate and gamma-aminobutyric acid cotransmission convey discrete patterns of dopamine neuron activity to striatal neurons. Glutamate may function not only in a signaling role at a subset of dopamine neuron synapses, but also in mediating vesicular synergy, contributing to regional differences in loading of dopamine into synaptic vesicles. Regional differences in dopamine neuron signaling are likely to be differentially involved in the schizophrenia disease process and likely determine the subregional specificity of the action of psychostimulants that exacerbate the disorder, and antipsychotics that ameliorate the disorder. Elucidating dopamine neuron synaptic signaling offers the potential for achieving greater pharmacological specificity through intersectional pharmacological actions targeting subsets of dopamine neuron synapses.

Keywords: Corelease; Cotransmission; GABA; Glutamate; Nucleus accumbens; Optogenetics; Vesicular synergy.

Fig 1. Functional subdivisions of the striatum in humans and rodents

Functionally, the striatum (Str) can be divided into corresponding limbic (magenta), associative (green) and sensorimotor (blue) regions, in both human (left) and rodent (right), determined by cortical inputs mediating each function. The schematics shown are midway along the anterior-posterior axis; there are substantial phylogenetic differences both anteriorly and posteriorly (25, 73). The NAc, which makes up the vStr is indicated by the dashed lines. In mouse, a second dashed line indicates the border between the accumbens core and shell. Orientation of sections is indicated by arrows. Abbreviations; Cd: caudate, Pu: putamen, NAc: nucleus accumbens, dStr: dorsal striatum, OT: olfactory tubercle. Striatal outlines are modified from atlases (135, 136).

Fig 2. Topography of midbrain dopamine neuron projections to the striatum in rodents

DA neurons project topographically (indicated by color spectrum) along the medial-lateral axis. More medially located DA neurons in the VTA project to the ventral Str, the NAc medial shell and medial OT. More laterally located DA neurons project to more dorsolateral Str (33). The topography extends to primates (137).

Fig 3. Heterogeneity in DA neuron synaptic actions in the mouse striatum

Optogenetic stimulation of DA neuron terminals elicits fast synaptic responses in principal Str neurons, spiny projection neurons (SPNs) and cholinergic interneurons (ChIs). The relative strength of each transmitter response in different Str regions is shown in pie charts. For reports without details of recording locations, the pie chart is located at the center of the region (e.g., dStr, Ref. 56). Responses seen in each area are schematized in pie charts by color: DA D2 receptor (dark green), DA D1 receptor (light green), GABAA receptor (dark blue), ionotropic glutamate receptor (magenta), and unknown excitatory transmitter (gray). Striatal outlines are the same as used in Figure 1. The schemes are a compendium of the several optogenetic studies (, , –68).