Neurexins contribute to inhibitory connectivity and dopamine neuron resilience in culture

Charles Ducrot, Alex Tchung, Samuel Burke, Consiglia Pacelli, Louis-Éric Trudeau
Neuroscience. 2026-08-01; 609: 84-92
DOI: 10.1016/j.neuroscience.2026.05.022

Ducrot C(1), Tchung A(2), Burke S(3), Pacelli C(4), Trudeau LÉ(5).

Author information:
(1)Department of Pharmacology and Physiology, Faculty of Medicine, Université de
Montréal, Canada; Department of Neurosciences, Faculty of Medicine, Université
de Montréal, Canada; Neural Signaling and Circuitry Research Group (SNC),
Canada. Electronic address: .
(2)Department of Pharmacology and Physiology, Faculty of Medicine, Université de
Montréal, Canada; Department of Neurosciences, Faculty of Medicine, Université
de Montréal, Canada; Neural Signaling and Circuitry Research Group (SNC),
Canada; Center for Interdisciplinary Research on the Brain and Learning (CIRCA),
Canada; Institut Courtois d’Innovation Biomédicale (CI2B), Montréal, QC H3C 3J7,
Canada.
(3)Department of Pharmacology and Physiology, Faculty of Medicine, Université de
Montréal, Canada; Department of Neurosciences, Faculty of Medicine, Université
de Montréal, Canada; Neural Signaling and Circuitry Research Group (SNC),
Canada.
(4)Department of Clinical and Experimental Medicine, University of Foggia,
Italy.
(5)Department of Pharmacology and Physiology, Faculty of Medicine, Université de
Montréal, Canada; Department of Neurosciences, Faculty of Medicine, Université
de Montréal, Canada; Neural Signaling and Circuitry Research Group (SNC),
Canada; Center for Interdisciplinary Research on the Brain and Learning (CIRCA),
Canada; Institut Courtois d’Innovation Biomédicale (CI2B), Montréal, QC H3C 3J7,
Canada. Electronic address: .

Midbrain dopamine (DA) neurons are essential regulators of basal ganglia
functions. Their axonal structure is intricate, with numerous non-synaptic
release sites and fewer synaptic terminals that notably release glutamate or
GABA. Despite their significance, the molecular mechanisms governing DA neuron
connectivity and neurochemical identity remain poorly understood. We hypothesize
that trans-synaptic cell adhesion molecules such as neurexins (Nrxns) regulate
the interactions of DA neuron axons with target cells and thereby influence
axonal branching and synapse formation by DA neurons. We therefore examined
neuronal survival, axonal growth and synapse formation in cultured DA neurons
lacking all neurexins (DAT::NrxnsKO). Conditional deletion of all Nrxns in DA
neurons revealed that loss of Nrxns does not disrupt the basic development of
these neurons or the structure of their axonal terminals, including normal
expression of the vesicular monoamine transporter (VMAT2) and the calcium sensor
synaptotagmin 1 (Syt1). However, we observed a reduction in the number of
TH-positive DA neurons in culture, suggesting altered resilience or increased
vulnerability under in vitro conditions. In addition, loss of Nrxns selectively
reduced the proportion of DA neuron terminals associated with the inhibitory
postsynaptic marker gephyrin, while the association with excitatory synaptic
markers was preserved.