Conditional deletion of neurexins dysregulates neurotransmission from dopamine neurons

• Published in: eLife Vol. 12
• Main Authors: Ducrot, Charles, de Carvalho, Gregory, Delignat-Lavaud, Benoît, Delmas, Constantin V L, Halder, Priyabrata, Giguère, Nicolas, Pacelli, Consiglia, Mukherjee, Sriparna, Bourque, Marie-Josée, Parent, Martin, Chen, Lulu Y, Trudeau, Louis-Eric
• Format: Journal Article
• Language: English
• Published: England eLife Science Publications, Ltd 06.07.2023; eLife Sciences Publications Ltd; eLife Sciences Publications, Ltd
• Subjects: Amphetamines; Animals; Axons; Basal ganglia; Cell adhesion & migration; Cell adhesion molecules; Central Nervous System Stimulants; co-transmission; Connectivity; Dopamine; Dopamine transporter; Dopaminergic Neurons - metabolism; GABA; gamma-Aminobutyric Acid - metabolism; Glutamate; Mesencephalon; Mice; Molecular modelling; Motor ability; Neostriatum; Neural networks; neurexins; Neurons; Neuroscience; Neurotransmission; Phenols; Presynaptic Terminals; Scientific equipment and supplies industry; synaptic terminals; Synaptic Transmission - physiology; Vesicular monoamine transporter 2; γ-Aminobutyric acid; United States; neurexins; co-transmission; mouse; neuroscience; GABA; dopamine; synaptic terminals
• ISSN: 2050-084X; 2050-084X
• DOI: 10.7554/eLife.87902

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 in addition to DA, glutamate or GABA are also released. The molecular mechanisms regulating the connectivity of DA neurons and their neurochemical identity are unknown. An emerging literature suggests that neuroligins, trans-synaptic cell adhesion molecules, regulate both DA neuron connectivity and neurotransmission. However, the contribution of their major interaction partners, neurexins (Nrxns), is unexplored. Here, we tested the hypothesis that Nrxns regulate DA neuron neurotransmission. Mice with conditional deletion of all Nrxns in DA neurons (DAT::NrxnsKO) exhibited normal basic motor functions. However, they showed an impaired locomotor response to the psychostimulant amphetamine. In line with an alteration in DA neurotransmission, decreased levels of the membrane DA transporter (DAT) and increased levels of the vesicular monoamine transporter (VMAT2) were detected in the striatum of DAT::NrxnsKO mice, along with reduced activity-dependent DA release. Strikingly, electrophysiological recordings revealed an increase of GABA co-release from DA neuron axons in the striatum of these mice. Together, these findings suggest that Nrxns act as regulators of the functional connectivity of DA neurons.