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”.
Highlights
Accumulating evidence implicates dysfunction within glutamatergic systems and dysregulation of synaptic plasticity in the pathophysiology of depression [1,2,3,4,5,6,7]
Ketamine (5 mg/kg, ip) significantly decreased day2 forced swim test (FST) immobility in both strains compared to their corresponding saline-treated controls at 30 min and 24 h after injection, with drug effects being comparable at 30 min and 24 h (Fig. 1a, b)
Following a low-frequency stimulation protocol (3 Hz, 900 pulses, 5 min), average Field excitatory postsynaptic potentials (fEPSP) slope was transiently reduced in all rats; we failed to detect any robust or long-lasting long-term depression (LTD) in either strain (5 min pre- vs. 30 min post- Low frequency stimulation (LFS), Tukey’s p > 0.83, n.s.; 30 min post-LFS WKY vs. WIS, Sidak’s p = 0.77, n.s.) (Fig. 2b), indicating no significant facilitation of LTD in stress-prone WKY rats
Summary
Accumulating evidence implicates dysfunction within glutamatergic systems and dysregulation of synaptic plasticity in the pathophysiology of depression [1,2,3,4,5,6,7]. Depressed patients show significant grey matter volume reductions, in the HPC and PFC, as well as various cognitive deficits (e.g. in attention, episodic memory and executive function) [3, 7, 11,12,13,14]. These effects, along with the core symptoms of emotional dysregulation and anhedonia [15,16,17], could all be mediated by impaired synaptic plasticity and loss of connectivity between key brain regions highly vulnerable to stress (for review, [7]). Further research is clearly needed to clarify the role of synaptic plasticity in the pathophysiology of depression and in mediating antidepressant response
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