Brimblecombe, K. R. | Search bioRxiv

bioRxiv2020

L-type calcium channel contribution to striatal dopamine release is governed by calbindin-D28K, the dopamine transporter, D2-receptors, α2δ-subunits and sex differences

Ca2+ entry into nigrostriatal dopamine (DA) neurons and axons via L-type voltage-gated Ca2+ channels (LTCCs) contributes respectively to pacemaker activity and DA release, and has long been thought to contribute to vulnerability to degeneration in Parkinsons disease. LTCC function is greater in DA axons and neurons from substantia nigra pars compacta than from ventral tegmental area, but this is not explained by channel expression level. We tested the hypothesis that LTCC-control of DA release is governed rather by local mechanisms, focussing on candidate biological factors known to operate differently between types of DA neurons and/or be associated with their differing vulnerability to parkinsonism, including biological sex, -synuclein, DA transporters (DATs), and calbindin-D28k (Calb1). We detected evoked DA release ex vivo in mouse striatal slices using fast-scan cyclic voltammetry, and assessed LTCC support of DA release by detecting the inhibition of DA release by the LTCC inhibitors isradipine or CP8. Using genetic knockouts or pharmacological manipulations we identified that striatal LTCC support of DA release depended on multiple intersecting factors, in a regionally and sexually divergent manner. LTCC function was promoted by factors associated with Parkinsonian risk, including male sex, -synuclein, DAT, and a dorsolateral co-ordinate, but limited by factors associated with protection i.e. female sex, glucocerebrosidase activity, Calb1, and ventromedial co-ordinate. Together, these data show that LTCC function in DA axons, and isradipine effect, are locally governed and suggest they vary in a manner that in turn might impact on, or reflect, the cellular stress that leads to parkinsonian degeneration. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=133 SRC="FIGDIR/small/186411v2_ufig1.gif" ALT="Figure 1"> View larger version (21K): org.highwire.dtl.DTLVardef@1ccc783org.highwire.dtl.DTLVardef@13e7296org.highwire.dtl.DTLVardef@d4e3d3org.highwire.dtl.DTLVardef@b9427b_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

bioRxiv2019

Astrocytic striatal GABA transporter activity governs dopamine release and shows maladaptive downregulation in early parkinsonism

Striatal dopamine (DA) is critical for action and learning. Recent data show DA release is under tonic inhibition by striatal GABA. Ambient striatal GABA tone on striatal projection neurons can be governed by plasma membrane GABA uptake transporters (GATs) on astrocytes. However, whether striatal GATs and astrocytes determine DA output are unknown. We reveal that DA release in mouse dorsolateral striatum, but not nucleus accumbens core, is governed by GAT-1 and GAT-3. These GATs are partly localized to astrocytes, and are enriched in dorsolateral striatum compared to accumbens core. In a mouse model of early parkinsonism, GATs were downregulated and tonic GABAergic inhibition of DA release augmented, with corresponding attenuation of GABA co-release from dopaminergic axons. These data define previously unappreciated and important roles for GATs and astrocytes in determining DA release in striatum, and reveal a maladaptive plasticity in early parkinsonism that impairs DA output in vulnerable striatal regions. HighlightsO_LIGABA transporters set the level of GABA inhibition of DA output in dorsal striatum C_LIO_LIAstrocytes facilitate DA release levels by limiting tonic GABA inhibition C_LIO_LITonic inhibition of DA release is augmented in a mouse model of early parkinsonism C_LIO_LIDA and GABA co-release are reduced in a mouse model of early parkinsonism C_LI

neuroscience↗