Ketamine induced synaptic plasticity operates independently of long-term potentiation.

Synaptic plasticity includes both homeostatic and Hebbian mechanisms that regulate AMPA receptor activity and glutamatergic transmission. Ketamine, a rapidly acting antidepressant, induces homeostatic plasticity to increase glutamatergic transmission. This study demonstrates that Hebbian plasticity, specifically long-term potentiation (LTP), remains intact in synapses that have undergone homeostatic scaling induced by ketamine, whether delivered systemically or perfused onto hippocampal brain slices. In mice exposed to chronic corticosterone (CORT) to model stress, CORT produced an anhedonia-like behavior but did not impair LTP induction. CORT exposure also did not disrupt the interaction between homeostatic and Hebbian plasticity; synapses from CORT-exposed mice showed intact ketamine-induced plasticity followed by LTP. These findings explain how ketamine treatment for depression does not compromise learning and memory processes that rely on LTP.

Study at a glance

Abstract

Synaptic plasticity occurs via multiple mechanisms to regulate synaptic efficacy. Homeostatic and Hebbian plasticity are two such mechanisms by which neuronal synapses can be altered. Although these two processes are mechanistically distinct, they converge on downstream regulation of AMPA receptor activity to modify glutamatergic neurotransmission. However, much remains to be explored regarding how these two prominent forms of plasticity interact. Ketamine, a rapidly acting antidepressant, increases glutamatergic transmission via pharmacologically-induced homeostatic plasticity. Here, we demonstrate that Hebbian plasticity mechanisms are still intact in synapses that have undergone homeostatic scaling by ketamine after either systemic injection or perfusion onto hippocampal brain slices. We also investigated this relationship in the context of stress induced by chronic exposure to corticosterone (CORT) to better model the circumstances under which ketamine may be used as an antidepressant. We found that CORT induced an anhedonia-like behavioral phenotype in mice but did not impair long-term potentiation (LTP) induction. Furthermore, corticosterone exposure does not impact the intersection of homeostatic and Hebbian plasticity mechanisms, as synapses from CORT-exposed mice also demonstrated intact ketamine-induced plasticity and LTP in succession. These results provide a mechanistic explanation for how ketamine used for the treatment of depression does not impair the integrity of learning and memory processes encoded by mechanisms such as LTP.