Mechanisms governing the development of synaptic transmission in the lateral habenula

The lateral habenula (LHb) is a key brain region involved in processing negative stimuli and adaptive responses to aversive situations. While LHb function in adulthood is well characterized, how its synaptic properties evolve during development remains unclear. Perineuronal nets (PNNs), extracellular matrix structures known to regulate synaptic maturation in other brain regions, progressively accumulate in the LHb during development and are altered by negative experiences, suggesting their potential role in LHb synaptic function regulation. Using in vitro electrophysiology in acute brain slices, we show that excitatory synaptic transmission in the LHb differs between young and adult mice. Young mice display lower AMPA/NMDA ratios, slower NMDA receptor kinetics although similar subunit composition. Additionally, they show reduced spontaneous activity, and weaker burst firing. Importantly, degrading PNNs in adulthood recapitulates the AMPA/NMDA synaptic feature of LHb in young individuals. Behaviorally, PNN degradation in the LHb did not alter active avoidance or escape behaviors but modified behavioral strategies in an anxiety-related task. Together, these findings identify developmental changes in LHb excitatory transmission and support a role for PNNs in stabilizing synaptic function and regulating negative affect-related behaviors.