Ketamine and its metabolite, (2R,6R)-HNK, restore hippocampal LTP and long-term spatial memory in the Wistar-Kyoto rat model of depression

Abstract

Accumulating evidence implicates dysregulation of hippocampal synaptic plasticity in the pathophysiology of depression. However, the effects of ketamine on synaptic plasticity and their contribution to its mechanism of action as an antidepressant, are still unclear. We investigated ketamine’s effects on in vivo dorsal hippocampal (dHPC) synaptic plasticity and their role in mediating aspects of antidepressant activity in the Wistar-Kyoto (WKY) model of depression. dHPC long-term potentiation (LTP) was significantly impaired in WKY rats compared to Wistar controls. Importantly, a single low dose (5 mg/kg, ip) of ketamine or its metabolite, (2R,6R)-HNK, rescued the LTP deficit in WKY rats at 3.5 h but not 30 min following injection, with residual effects at 24 h, indicating a delayed, sustained facilitatory effect on dHPC synaptic plasticity. Consistent with the observed dHPC LTP deficit, WKY rats exhibited impaired hippocampal-dependent long-term spatial memory as measured by the novel object location recognition test (NOLRT), which was effectively restored by pre-treatment with both ketamine or (2R,6R)-HNK. In contrast, in WKYs, which display abnormal stress coping, ketamine, but not (2R,6R)-HNK, had rapid and sustained effects in the forced swim test (FST), a commonly used preclinical screen for antidepressant-like activity. The differential effects of (2R,6R)-HNK observed here reveal a dissociation between drug effects on FST immobility and dHPC synaptic plasticity. Therefore, in the WKY rat model, restoring dHPC LTP was not correlated with ketamine’s effects in FST, but importantly, may have contributed to the reversal of hippocampal-dependent cognitive deficits, which are critical features of clinical depression. Our findings support 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”.

(R,S)-ketamine and (2R,6R)-hydroxynorketamine differentially affect memory as a function of dosing frequency

“…Importantly, clinical status moderates the extent to which an individual will experience changes in cognition following ketamine exposure [ 19 ]. Single and repeated ketamine administration exerts pro-cognitive effects in preclinical models of depressive-like behavior [ 98 – 101 ] and in patients with treatment-resistant major depression [ 6 , 21 , 23 , 40 ], especially those suffering from comorbid anxiety [ 40 ]. The cognition-enhancing properties of ketamine observed in patients suffering from depression may be explained by the fact that many of these patients show baseline cognitive deficits [ 24 , 25 ] and may be related at least in part to its antidepressant actions [ 23 , 28 , 29 ].…”

A translational perspective on the anti-anhedonic effect of ketamine and its neural underpinnings

“…Thus far, we have reviewed evidence that describes the habenula's role in the processing of reward and punishment as well as its contribution to analogues of depressive behaviours, mostly based on findings from rodent studies [7,34,[42][43][44]. One intriguing finding from the rodent literature demonstrated that acute stress can reverse the activity of reward selective neurons in the lHb [42], such that they respond to rewards as though they were punishing.…”

Ketamine and Calcium Signaling—A Crosstalk for Neuronal Physiology and Pathology

“…It is well-documented that depression is caused by complex pathological processes in certain brain regions (hippocampus, prefrontal cortex, amygdale), triggered by dysregulation of a variety of signaling pathways (many of them yet unidentified), and characterized by decreased neuronal branching and plasticity in the hippocampus [155]. Prolonged stress conditions can impair LTP and enhance LTD in rat hippocampus [156]. A number of reports have shown that ketamine can alter the activity of several important components of synaptic transmission that contribute to LTP and LTD induction or maintenance under depression-induced memory dysfunction.…”