Implication of synaptotagmins 4 and 7 in activity-dependent somatodendritic dopamine release

Abstract

Dopamine (DA) neurons can release DA not just from axon terminals, but also from their somatodendritic (STD) compartment thought a mechanism that is still incompletely understood. Using voltammetry in mouse mesencephalic brain slices, we find that STD DA release has low capacity, is stable in response to electrical but not optogenetic train pulses and shows a calcium sensitivity that is comparable to that of axonal release. It is also strikingly more resilient compared to axonal release in a 6‐ hydroxydopamine model of Parkinson’s disease plasticity. We find that the molecular mechanism of STD DA release differs from axonal release with regards to the implication of synaptotagmin (Syt) calcium sensors. While individual constitutive knock-out Syt4 and Syt7 is not sufficient to reduce STD DA release, removal of both isoforms reduces this release by ~50%, leaving axonal release unimpaired. Our works unveils clear differences in the mechanisms of STD and axonal DA release.

Subcellular proteomics of dopamine neurons in the mouse brain reveals axonal enrichment of proteins encoded by Parkinson’s disease-linked genes

“…These data support the recent finding that Syt-1 is the major fast Ca 2+ sensor for synchronous DA release (Banerjee, Lee, et al, 2020). In addition to the established role of Syt-7 in somatodendritic DA release and the observation of its presence in DA axon terminals (Delignat-Lavaud et al, 2021;Mendez et al, 2011), our findings support Syt-7 as a candidate protein for asynchronous axonal DA release (Banerjee, Lee, et al, 2020). These data highlight candidate proteins for further investigation and provide a proteomic architecture of the dopaminergic presynapse that is highly consistent with recent functional studies (Banerjee, Imig, et al, 2020;Banerjee, Lee, et al, 2020;C.…”

Synaptotagmin-1-dependent phasic axonal dopamine release is dispensable for basic motor behaviors in mice

“…In the VTA (Fig. 2D), the release of DA induced by optogenetic train stimulation with hChR2 was easily detectable and of an amplitude similar to previously reported (203 nM ± 13 nM, n = 5 mice) (Delignat-Lavaud et al, 2021). Release evoked by optogenetic stimulation with ChR2-Kv in Syt1 +/+ mice was significantly lower (132 nM ± 16 nM, n = 7 mice; 2-way ANOVA with Šidák, p <0.0001) compared to hChR2 (203 nM ± 13 nM, n = 5 mice) (Fig.…”

“…Because the available anatomical data suggests that DA containing axonal varicosities are extremely scarce in the SNc and VTA except in the context of compensatory axonal sprouting associated with partial lesions (Fernandes Xavier et al, 1994), it would be important to revisit this question in the future with a more thorough anatomical investigation. The novel optogenetic approach described here in order to trigger STD DA release more selectively should be very useful in the future to further explore the distinct molecular machinery involved in STD and axonal DA release so as to extend recent work showing a role for Syt4 and Syt7 isoforms in this process (Mendez et al, 2011;Delignat-Lavaud et al, 2021).…”

“…A 65 amino acid motif of the Kv2.1 voltage-gated potassium channel fused with the carboxy terminus of ChR2-EYFP (Baker et al, 2016) was inserted in a Cre-dependent AAV vector (AAV2/5-hsyn-DIO-ChR2-eYFP-Kv). A standard cell-wide hChR2 (AAV2/5-hsyn-DIO-ChR2-eYFP), previously used to trigger DA release in the striatum (O'Neill et al, 2017) and mesencephalon (Delignat-Lavaud et al, 2021) was used as a control.…”

“…Recent work has confirmed and extended this finding in the intact brain by showing that Syt1 is essential for evoked DA release (Banerjee et al, 2020b) . Syt4 and Syt7 were recently shown to control STD DA release, suggesting a distinct molecular machinery compared to axonal DA release (Mendez et al, 2011; Delignat-Lavaud et al, 2021) .…”