Neurexins Regulate GABA Co-release by Dopamine Neurons

Abstract

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) revealed 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 reveal that Nrxns act as key regulators of DA neuron connectivity and DA-mediated functions.

Advances in neurexin studies and the emerging role of neurexin-2 in autism spectrum disorder

“…In another study, the pan-Nrxn cKO approach in DA neurons reduced amphetamineinduced locomotor activity without affecting other striatal-dependent behaviors such as motor coordination or sucrose preference. This investigation suggests that DAT-IRES-Cre driven deletion of neurexin genes can impair DAT function (expressed on DA neurons) leading to altered behavioral responses to DA-acting drugs (Ducrot et al, 2021).…”

“…The study employed a pan-Nrxn cKO approach in four central synapses: excitatory Calyx of Held synapses in the brainstem, excitatory and inhibitory synapses in pyramidal neurons in the CA1 region of the hippocampus, and inhibitory basket cell synapses in the cerebellum, thus showing that neurexins universally regulate presynaptic GABA B -receptor signaling, albeit at different magnitude between synapses (Luo et al, 2021). More recent work shows that neurexins regulate GABA co-release in dopamine (DA) neurons (Ducrot et al, 2021). The pan-Nrxn cKO approach in DA neurons, showed (1) region-specific increase in GABA release from DA terminals (increase in the ventral but not in the dorsal striatum) and (2) slower DA reuptake along with decreased and increased densities of DA transporter (DAT) and vesicular monoamine transporter (VMAT2), respectively (Ducrot et al, 2021), indicating that neurexins support the functional but not the structural aspect of DA neuron synapses.…”

“…More recent work shows that neurexins regulate GABA co-release in dopamine (DA) neurons (Ducrot et al, 2021). The pan-Nrxn cKO approach in DA neurons, showed (1) region-specific increase in GABA release from DA terminals (increase in the ventral but not in the dorsal striatum) and (2) slower DA reuptake along with decreased and increased densities of DA transporter (DAT) and vesicular monoamine transporter (VMAT2), respectively (Ducrot et al, 2021), indicating that neurexins support the functional but not the structural aspect of DA neuron synapses. Utilization of the conditional deletion approach has 10.…”

“…Utilization of the conditional deletion approach has 10. 3389/fnmol.2023.1125087 Frontiers in Molecular Neuroscience 04 frontiersin.org enabled significant progress in our understanding of neurexins' function in specific synapses (Ducrot et al, 2021;Luo et al, 2021). This is important because the first study using the pan-Nrxn cKO approach in various types of synapses discovered severe, but dramatically different phenotypes (Chen et al, 2017).…”

Divergent properties and independent regulation of striatal dopamine and GABA co-transmission

“…Segregation of DA and glutamate within dopaminergic axonal terminals has been found to be induced by contact with ventral striatal neurons ( Fortin et al, 2019 ), which may underlie the differences in release and recycling properties of DA and glutamate ( Silm et al, 2019 ). Neurexins have recently been identified as key trans-synaptic regulators of DA transmission that also influence GABA co-transmission ( Ducrot et al, 2021 ). Several cytoskeletal proteins associate with D2 receptors, including actin binding proteins and spinophilin to control surface expression of receptors, maintain their density, and regulate receptor signaling ( Li et al, 2000 ; Smith et al, 1999 ).…”