MECHANISMS GOVERNING THE DEVELOPMENT OF SYNAPTIC TRANSMISSION IN THE LATERAL HABENULA

The lateral habenula (LHb) is a key brain node encoding negative stimuli and its synaptic function in adulthood supports the emergence of adaptive behavior in aversive contexts. However, it remains unknown how synaptic neurotransmission is established in the developing LHb to ensure its mature properties. In other brain structures, development of synaptic neurotransmission is tightly regulated by various elements including the perineuronal nets (PNNs), a form of extracellular matrix surrounding the somata and proximal dendrites of neurons. Notably, PNNs expression gradually increases in the LHb throughout brain maturation and is disrupted after experience of negative events. Together, these findings support the notion that, also in the LHb, PNNs can contribute to synaptic circuit establishment and, consequently, to the regulation of circuit function and behaviors.
Here, using in vitro electrophysiological recordings on acute brain slices, AMPA/NMDA ratios in the LHb were shown to differ between young and adult mice, with NMDA currents displaying slower decay kinetics at early stages. Additionally, disruption of the PNNs in adulthood recapitulated a synaptic phenotype resembling that observed of early development. Behaviorally, disruption of PNN in LHb did not affect active avoidance learning nor inescapable footshock escape. However, mice behavioral strategy adapted in an anxiety-testing paradigm following PNN degradation.
In conclusion, our observations indicate that excitatory synapses in the LHb change their properties across developmental periods and support PNNs as stabilizers of synaptic function and modulators of negative affect related behavior.