Biology subjects

Giguere, N.

Publications and source records attributed to Giguere, N..

3 recordsLinked to original sources

bioRxiv2021

Neurexins Regulate GABA Co-release by Dopamine Neurons

Midbrain dopamine (DA) neurons are key regulators of basal ganglia functions. The axonal domain of these neurons is highly complex, with a large subset of non-synaptic release sites and a smaller subset of synaptic terminals from which glutamate or GABA are released. The molecular mechanisms regulating the connectivity of DA neurons and their neurochemical identity are unknown. Here we tested the hypothesis that the trans-synaptic cell adhesion molecules neurexins (Nrxns) regulate DA neuron neurotransmission. Conditional deletion of all Nrxns in DA neurons (DAT::Nrxns KO) showed that loss of Nrxns does not impair the basic development and ultrastructural characteristics of DA neuron terminals. However, loss of Nrxns caused an impairment of DA transmission revealed as a reduced rate of DA reuptake following activity-dependent DA release, decreased DA transporter levels, increased vesicular monoamine transporter expression, and impaired amphetamine-induced locomotor activity. Strikingly, electrophysiological recording revealed an increase of GABA co-release from DA neuron axons in the striatum of the KO mice. These findings suggest that Nrxns act as key regulators of DA neuron connectivity and DA-mediated functions. HighlightsO_LIThe study provides the first direct evidence of the role of neurexins in dopaminergic neurons. C_LIO_LIThe synaptic adhesion molecules, neurexins, are not required for maintaining the structure of dopamine neuron terminals. C_LIO_LINeurexins regulate dopaminergic neurotransmission through regulation of dopamine reuptake, impacting amphetamine-induced locomotion. C_LIO_LIDeletion of Nrxns in DA neurons causes a region-specific increase of GABA release by DA neurons. C_LI

neuroscience↗

bioRxiv2021

The calcium sensor synaptotagmin-1 is critical for phasic axonal dopamine release in the striatum and mesencephalon, but is dispensable for basic motor behaviors in mice

In Parkinsons disease (PD), motor dysfunctions only become apparent after extensive loss of DA innervation. This resilience has been hypothesized to be due to the ability of many motor behaviors to be sustained through a diffuse basal tone of DA; but experimental evidence for this is limited. Here we show that conditional deletion of the calcium sensor synaptotagmin-1 (Syt1) in DA neurons (Syt1 cKODA mice) abrogates most activity-dependent axonal DA release in the striatum and mesencephalon, leaving somatodendritic (STD) DA release intact. Strikingly, Syt1 cKODA mice showed intact performance in multiple unconditioned DA-dependent motor tasks and even in a task evaluating conditioned motivation for food. Considering that basal extracellular DA levels in the striatum were unchanged, our findings suggest that activity-dependent DA release is dispensable for such tasks and that they can be sustained by a basal tone of extracellular DA. Taken together, our findings reveal the striking resilience of DA-dependent motor functions in the context of a near-abolition of phasic DA release, shedding new light on why extensive loss of DA innervation is required to reveal motor dysfunctions in PD.

neuroscience↗

bioRxiv2021

Neonatal 6-OHDA lesion of the SNc induces striatal compensatory sprouting from surviving SNc dopaminergic neurons without VTA contribution

Dopamine (DA) neurons of the substantia nigra pars compacta (SNc) are uniquely vulnerable to neurodegeneration in Parkinsons disease (PD). We hypothesize that their large axonal arbor is a key factor underlying their vulnerability, due to increased bioenergetic, proteostatic and oxidative stress. In keeping with this model, other DAergic populations with smaller axonal arbors are mostly spared during the course of PD and are more resistant to experimental lesions in animal models. Aiming to improve mouse PD models, we examined if neonatal partial SNc lesions could lead to adult mice with fewer SNc DA neurons that are endowed with larger axonal arbors because of compensatory mechanisms. We injected 6-hydroxydopamine (6-OHDA) unilaterally in the SNc at an early postnatal stage at a dose selected to induce loss of approximately 50% of SNc DA neurons. We find that at 10- and 90-days after the lesion, the axons of SNc DA neurons show massive compensatory sprouting, as revealed by the proportionally smaller decrease in tyrosine hydroxylase (TH) in the striatum compared to the loss of SNc DA neuron cell bodies. The extent and origin of this axonal sprouting was further investigated by AAV-mediated expression of eYFP in SNc or ventral tegmental area (VTA) DA neurons of adult mice. Our results reveal that SNc DA neurons have the capacity to substantially increase their axonal arbor size and suggest that mice designed to have reduced numbers of SNc DA neurons could potentially be used to develop better mouse models of PD, with elevated neuronal vulnerability. Graphical abstract textO_LIWe describe a technique to induce the loss of approximately 50% of SNc DA neurons in neonate mice using unilateral intranigral 6-OHDA (left panel). C_LIO_LICompensatory axonal sprouting was observed in the striatum as early as 10 days following the lesion (at P15), with effects lasting until adulthood (P90). C_LIO_LIConditional AAV-mediated expression of eYFP (green) reveals SNc DA neurons, projecting to the dorsal striatum (middle panel), and not VTA DA neurons, projecting to the ventral striatum (right panel), as the main source of compensatory axonal sprouting. C_LI Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=98 SRC="FIGDIR/small/437271v1_ufig1.gif" ALT="Figure 1"> View larger version (29K): org.highwire.dtl.DTLVardef@5febf7org.highwire.dtl.DTLVardef@17cc625org.highwire.dtl.DTLVardef@b4d509org.highwire.dtl.DTLVardef@e496a_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗