(109) - Trans-synaptic regulation of sensory circuit connectivity in the spinal cord by neurexins and neuroligins

Abstract

Rapid processing and integration of sensory information is critical for survival, and permits the discrimination of a tremendous variety of external inputs. However, sensory circuits can become activated in the absence of noxious events, leading to chronic pain states. While plasticity of nociceptive transmission is well-established, we possess a limited understanding of the underlying molecular mechanisms which orchestrate the proper wiring of these circuits. Trans-synaptic interactions between presynaptic neurexins and postsynaptic neuroligins have been suggested to impart a combinatorial code for neural connectivity. In the peripheral nervous system, sensory neurons do not form synapses with each other in culture, suggesting that they lack key signals involved in determining appropriate synaptic partners. To understand the mechanisms governing synaptic connectivity in the somatosensory system, we co-cultured fibroblasts expressing different adhesion molecules with both mouse and human sensory neurons. We found that expression of all neuroligin isoforms and splice variants strongly promoted functional glutamatergic synapse formation. In contrast, neurexins were ineffective at inducing presynaptic contacts. Over-expression of neurexins or neuroligins were unable to induce autaptic connections, suggesting that both attractive and repulsive mechanisms exist to specify synapse formation. To understand how these molecules regulate the wiring of somatosensory circuits, we employed a conditional gene deletion strategy in mice. We found that the loss of beta-neurexins in Nav1.8+ sensory neurons led to modality-specific alterations in sensory behaviors. While these manipulations did not alter mechanical or heat sensitivity, mice exhibited an increased sensitivity to cold. Despite normal heat thresholds, inflammation-induced thermal hypersensitivity was completely absent. To understand how beta-neurexins regulate synaptic plasticity and connectivity, we created conditional optogenetic knockout lines to selectively stimulate fibers lacking beta-neurexins. In spinal cord slices, beta-neurexin deletion weakens synaptic transmission and decreases synaptic connectivity. We are now trying to understand how these molecules underlie modality-specific sensory behaviors.