Ketamine Protects Gamma Oscillations by Inhibiting Hippocampal LTD

Huang, Lan-Ting; Yang, Xudong; Huang, Ying; Sun, Eve Y.; Sun, Mu

doi:10.1371/journal.pone.0159192

Cited by 12 publications

(7 citation statements)

References 68 publications

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“…An alternative explanation is that g oscillatory activity not only has an effect on LTP-like phenomena, but also modulates the physiological mechanisms responsible for LTD-like plasticity. This hypothesis is supported by recent evidence from animal and human studies [15,46]. Huang and colleagues [46] demonstrated that N-methyl-Daspartate (NMDA)-induced LTD produces a reduction of g oscillatory activity in mouse cortex.…”

Section: Discussionmentioning

confidence: 79%

LTD-like plasticity of the human primary motor cortex can be reversed by γ-tACS

et al. 2019

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Section: Discussionmentioning

confidence: 79%

LTD-like plasticity of the human primary motor cortex can be reversed by γ-tACS

et al. 2019

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“…Due to the low intensity of the stimulation, we may speculate that alternating currents reached the more external layer of cerebellum where Purkinje cells have their bodies [41]. By modulating the activity of these cells in the cerebellar cortex, gamma-tACS might have prevented the LTD processes needed for the formation of internal models and consequently for sequence learning [42,43]. Indeed, inducing gamma oscillations might have led to long-term potentiation (LTP) [44].…”

Section: Discussionmentioning

confidence: 99%

Functional Role of Cerebellar Gamma Frequency in Motor Sequences Learning: a tACS Study

et al. 2021

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Although the role of the cerebellum in motor sequences learning is widely established, the specific function of its gamma oscillatory activity still remains unclear. In the present study, gamma (50 Hz)—or delta (1 Hz)—transcranial alternating current stimulation (tACS) was applied to the right cerebellar cortex while participants performed an implicit serial reaction time task (SRTT) with their right hand. The task required the execution of motor sequences simultaneously with the presentation of a series of visual stimuli. The same sequence was repeated across multiple task blocks (from blocks 2 to 5 and from blocks 7 to 8), whereas in other blocks, new/pseudorandom sequences were reproduced (blocks 1 and 6). Task performance was examined before and during tACS. To test possible after-effects of cerebellar tACS on the contralateral primary motor cortex (M1), corticospinal excitability was assessed by examining the amplitude of motor potentials (MEP) evoked by single-pulse transcranial magnetic stimulation (TMS). Compared with delta stimulation, gamma-tACS applied during the SRTT impaired participants’ performance in blocks where the same motor sequence was repeated but not in blocks where the new pseudorandom sequences were presented. Noteworthy, the later assessed corticospinal excitability was not affected. These results suggest that cerebellar gamma oscillations mediate the implicit acquisition of motor sequences but do not affect task execution itself. Overall, this study provides evidence of a specific role of cerebellar gamma oscillatory activity in implicit motor learning.

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“…e Average total distance travelled in the OFT for saline and (2R,6R)-HNK treated WKY rats (n = 6/group) at 30 min or 24 h post-injection, where HNK had no effects on WKY general locomotor activity. *p ≤ 0.05, **p ≤ 0.01, ***p ≤ 0.001 51,54], effects which seem to be in line with ketamine's action as an open-channel NMDAR antagonist. However, importantly, others have previously no change [49,50] or even a facilitation of LTP [55][56][57] in the rodent HPC following ketamine.…”

Section: Discussionmentioning

confidence: 55%

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

Aleksandrova¹,

Wang²,

Phillips³

2020

Mol Brain

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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”.

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Ketamine Protects Gamma Oscillations by Inhibiting Hippocampal LTD

Cited by 12 publications

References 68 publications

LTD-like plasticity of the human primary motor cortex can be reversed by γ-tACS

LTD-like plasticity of the human primary motor cortex can be reversed by γ-tACS

Functional Role of Cerebellar Gamma Frequency in Motor Sequences Learning: a tACS Study

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

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