Biology subjects

Somayaji, M.

Publications and source records attributed to Somayaji, M..

4 recordsLinked to original sources

bioRxiv2022

Novel Computational Models of Evoked Dopamine Release In Vivo Measured by Fast Scan Cyclic Voltammetry Quantify the Regulation of Presynaptic Kinetics by Synucleins

Dopamine neurotransmission in the striatum is central to many normal and disease functions. Ventral midbrain dopamine neurons exhibit ongoing tonic firing that produce low extrasynaptic levels of dopamine below the detection of extrasynaptic electrochemical recordings ([~]10 - 20 nanomolar), with superimposed bursts that can saturate the dopamine uptake transporter and produce transient micromolar concentrations. The bursts have previously been shown to lead to presynaptic plasticity via multiple mechanisms, but analysis methods for these kinetic parameters are limited. To provide a deeper understanding of the mechanics of dopamine neurotransmission, we present three computational models of dopamine release with different levels of spatiotemporal complexity to analyze in vivo fast-scan cyclic voltammetry recordings from the dorsal striatum of mice. The models accurately fit to the cyclic voltammetry data and provide estimates of presynaptic dopamine facilitation/depression kinetics and dopamine transporter reuptake kinetics. We use the models to analyze the role of synuclein proteins in neurotransmission and quantify recent findings linking presynaptic protein -synuclein to the short-term facilitation and long-term depression of dopamine release.

neuroscience↗

bioRxiv2022

Dopamine transporter and synaptic vesicle sorting defects initiate auxilin-linked Parkinson's disease

Auxilin participates in the uncoating of clathrin-coated vesicles (CCVs), thereby facilitating synaptic vesicle (SV) regeneration at presynaptic sites. Auxilin (DNAJC6/PARK19) loss-of- function mutations cause early-onset Parkinsons disease (PD). Here, we utilized auxilin-knockout (KO) mice to elucidate the mechanisms through which auxilin deficiency and clathrin-uncoating deficits lead to PD. We demonstrate that auxilin KO mice display the cardinal features of PD, including progressive motor deficits, -synuclein pathology, nigral dopaminergic loss, and neuroinflammation. Through unbiased proteomic and neurochemical analyses, we demonstrate that dopamine homeostasis is disrupted in auxilin KO brains, including via slower dopamine reuptake kinetics in vivo, an effect associated with dopamine transporter misrouting into axonal membrane deformities in the dorsal striatum. We also show that elevated macroautophagy and defective SV protein sorting contribute to ineffective dopamine sequestration and homeostasis, ultimately leading to neurodegeneration. This study advances our knowledge of how presynaptic endocytosis deficits lead to dopaminergic vulnerability and pathogenesis of PD.

neuroscience↗

bioRxiv2020

α-Synuclein facilitates dopamine release during burst firing of substantia nigra neurons in vivo

-Synuclein is expressed at high levels at presynaptic terminals, but defining its role on neurotransmission under physiologically-relevant conditions has proven elusive. We report that -synuclein is responsible for a rapid facilitation of dopamine release during action potential bursts in vivo. This occurs in tandem with a far slower stimulus-dependent depression, appears to be independent of the presence of {beta}- and {gamma}-synucleins or effects on presynaptic calcium and is consistent with a role for synucleins in the enhancement of synaptic vesicle fusion and turnover. The results indicate that the presynaptic effects of -synuclein are dependent on specific patterns of neuronal activity.

neuroscience↗

bioRxiv2019

In vivo functional diversity of midbrain dopamine neurons within identified axonal projections

The functional diversity of midbrain dopamine (DA) neurons ranges across multiple scales, from differences in intrinsic properties and synaptic connectivity to selective task engagement in behaving animals. Distinct in vitro biophysical features of DA neurons have been associated with different axonal projection targets. However, it is unknown how this translates to different firing patterns of projection-defined DA subpopulations in the intact brain. We combined retrograde tracing with single-unit recording and juxtacellular labelling in mouse brain to create the first single cell-resolved in vivo functional topography of the midbrain DA system. We identified surprising differences in burst firing among those DA neurons projecting to dorsolateral striatum, which were organized along the medio-lateral substantia nigra (SN) axis. Furthermore, burst properties also differentiated DA neurons in the medial SN that projected either to dorsal or ventral striatum. In contrast, DA neurons projecting to lateral shell of nucleus accumbens displayed identical firing properties, irrespective of whether they were located in the SN or ventral tegmental area (VTA), thus breaching classical anatomical boundaries. Finally, we found robust differences in mean firing rates and pause durations among VTA DA neurons projecting to either lateral or medial shell of nucleus accumbens. Together, our data set establishes a high-resolution functional landscape of midbrain DA neurons, which will facilitate the identification of selective functions and pathophysiological changes within the midbrain DA system.

neuroscience↗