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Characterization of the Wistar-Kyoto rat model of depression in the context of hippocampal synaptic plasticity and ketamine’s antidepressant properties

University of British Columbia

Accumulating evidence implicates dysfunction within the glutamatergic system and dysregulation of synaptic plasticity in the pathophysiology of depression, particularly in the hippocampus (HPC). Ketamine has rapid and sustained antidepressant activity in treatmentresistant depression and various animal models; however, its effects on synaptic plasticity, as well as their contribution to ketamine’s antidepressant action, are still unclear. To address this, we utilized the Wistar-Kyoto (WKY) model of endogenous stress susceptibility and depression. Consistent with the literature, WKY rats exhibited various depressive-like phenotypes compared to Wistar controls. In addition, we revealed that while in vivo hippocampal long-term depression (LTD) at the Schaffer collateral–CA1 (SC-CA1) synapse was not facilitated in the WKY strain, both early and late long-term potentiation (LTP) were significantly impaired. Importantly, both ketamine (5mg/kg, ip), as well as its metabolite (2R,6R)-HNK (5mg/kg, ip), acutely rescued the LTP deficit in WKYs at 3.5h following injection. Consistent with a sustained LTP-like effect, ketamine also increased SC-CA1 basal synaptic transmission at 24h in these rats. Importantly, ketamine, but not (2R,6R)-HNK, was found to have rapid and sustained antidepressant effects in WKY rats in the FST, leading to a dissociation between FST antidepressant-like activity and dorsal HPC synaptic plasticity. However, consistent with the observed SC-CA1 L-LTP deficit and corresponding effects of drug treatment, WKY rats exhibited impaired hippocampaldependent long-term spatial memory compared to Wistar controls (as measured by the novel object location recognition test at a delay of 24h), which was effectively restored by both ketamine and (2R,6R)-HNK. We propose that, in the WKY rat model, restoring dorsal HPC LTP does not underlie ketamine’s antidepressant effects in FST, but may instead mediate reversal of hippocampal-dependent cognitive deficits, which are also key features of clinical depression.iv This work supports the theory that ketamine may reverse the stress-induced loss of connectivity in key neural circuits by engaging synaptic plasticity processes to “reset the system”, and highlights the importance of deconstructing depression-like phenotypes and identifying the neural circuits that mediate them more precisely. Based on our results, the existing hypothesis that ketamine’s antidepressant effects are solely due to the actions of its metabolite (2R,6R)- HNK is effectively challenged.

Text

2019-10-04

Attribution-NonCommercial-NoDerivatives 4.0 International

http://hdl.handle.net/2429/71831

Neuroscience

University of British Columbia

UBCV

http://creativecommons.org/licenses/by-nc-nd/4.0/