A pilot randomized controlled trial of ketamine in Borderline Personality Disorder Sarah K Fineberg, Esther Y Choi, Rosa Shapiro-Thompson, Khushwant Dhaliwal, Eli Neustadter, Madison Sakheim, Kaylee Null, Daniel Trujillo-Diaz, Jocelyne Rondeau, Giana F Pittaro, Jessica R Peters, Philip R Corlett, John H Krystal. Neuropsychopharmacology. 2023 Feb 17. doi: 10.1038/s41386-023-01540-4. Epub ahead of print. PMID: 36804489. Presenter: Sarah Fineberg, MD, PhD Assistant Professor of Psychiatry, Yale School of Medicine Department of Psychiatry, New Haven, CT, USA.

Synaptic plasticity occurs via multiple mechanisms to regulate synaptic ef cacy. 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.

The NMDA antagonist S-ketamine is gaining increasing use as a rapid-acting antidepressant, although its exact mechanisms of action are still unknown. In this study, we investigated ketamine in respect to its properties toward central noradrenergic mechanisms and how they influence alertness behavior.