Neuroligin-3 Modulates Opioid-Evoked Changes in Behavior and Brain Function

Abstract

Chronic opioid exposure causes structural and functional changes in brain circuits, which may contribute to opioid use disorders. Synaptic cell-adhesion molecules are prime candidates for mediating this opioid-evoked plasticity. Neuroligin-3 is a postsynaptic adhesion protein that shapes synaptic function at multiple sites in the mesolimbic dopamine system. We therefore studied how genetic knockout of neuroligin-3 alters responses to chronic morphine in male mice. Constitutive neuroligin-3 knockout caused a persistent reduction in psychomotor sensitization after chronic morphine exposure, as well as a change in the topography of locomotor stimulation produced by morphine. This latter change was recapitulated by conditional genetic deletion of neuroligin-3 from cells expressing the Drd1 dopamine receptor, whereas the reduction in psychomotor sensitization was recapitulated by conditional genetic deletion from dopamine neurons. In the absence of neuroligin-3 expression, dopamine neurons within the ventral tegmental area showed diminished activation following chronic morphine exposure, as measured by in vivo calcium imaging with fiber photometry. This altered pattern of dopamine neuron activity may be driven by aberrant forms of opioid-evoked synaptic plasticity in the absence of neuroligin-3: dopamine neurons lacking neuroligin-3 showed weaker synaptic inhibition at baseline, which was subsequently strengthened after chronic morphine. In total, our study highlights neurobiological adaptations in dopamine neurons of the ventral tegmental area that correspond with increased behavioral sensitivity to opioids, and further suggests that neuroligin-3 expression by dopamine neurons provides a molecular substrate for opioid-evoked adaptations in brain function and behavior.