Long-Term Depression & Latent Inhibition

Research Paper Title

Disruption of long-term depression potentiates latent inhibition: Key role for central nucleus of the amygdala.

Background

Latent inhibition (LI) reflects an adaptive form of learning, which is impaired in certain forms of mental illness. Glutamate receptor activity is linked to LI, but the potential role of synaptic plasticity remains unspecified.

Methods

Accordingly, the present study examined the possible role of long-term depression (LTD) in LI induced by prior exposure of rats to an auditory stimulus used subsequently as a conditional stimulus (CS) to signal a pending footshock. The researchers employed two mechanistically distinct LTD inhibitors, the Tat-GluA23Y peptide that blocks endocytosis of the GluA2-containing glutamate α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR), or the selective glutamate n-methyl-d-aspartate receptor (NMDAR) 2B antagonist, Ro25-6981, administered prior to the acquisition of two-way conditioned avoidance with or without tone pre-exposure.

Results

Systemic LTD blockade with the Tat-GluA23Y peptide strengthened the LI effect by further impairing acquisition of conditioned avoidance in CS-pre-exposed rats compared to normal conditioning in non-pre-exposed controls. Systemic Ro25-6981 had no significant effects. Brain-region specific microinjections of the Tat-GluA23Y peptide into the nucleus accumbens, medial prefrontal cortex, central or basolateral amygdala demonstrated that disruption of AMPAR endocytosis in the central amygdala also potentiated the LI effect.

Conclusions

These data revealed a previously unknown role for central amygdala LTD in LI as a key mediator of cognitive flexibility required to respond to previously irrelevant stimuli that acquire significance through reinforcement. The findings may have relevance both for our mechanistic understanding of LI and its alteration in disease states such as schizophrenia, while further elucidating the role of LTD in learning and memory.

Reference

Ashby, D.M., Dias, C., Aleksandrova, L.R., Lapish, C.C., Wang, Y.T. & Phillips, A.G. (2021) Disruption of long-term depression potentiates latent inhibition: Key role for central nucleus of the amygdala. The International Journal of Neuropsychopharmacology. doi: 10.1093/ijnp/pyab011. Online ahead of print.