Long-term potentiation prevents ketamine-induced aberrant neurophysiological dynamics in the hippocampus-prefrontal cortex pathway in vivo

Abstract

N-methyl-D-aspartate receptor (NMDAr) antagonists such as ketamine (KET) produce psychotic-like behavior in both humans and animal models. NMDAr hypofunction affects normal oscillatory dynamics and synaptic plasticity in key brain regions related to schizophrenia, particularly in the hippocampus and the prefrontal cortex. It has been shown that prior long-term potentiation (LTP) occluded the increase of synaptic efficacy in the hippocampus-prefrontal cortex pathway induced by MK-801, a noncompetitive NMDAr antagonist. However, it is not clear whether LTP could also modulate aberrant oscillations and short-term plasticity disruptions induced by NMDAr antagonists. Thus, we tested whether LTP could mitigate the electrophysiological changes promoted by KET. We recorded HPC-PFC local field potentials and evoked responses in urethane anesthetized rats, before and after KET administration, preceded or not by LTP induction. Our results show that KET promotes an aberrant delta-high-gamma cross-frequency coupling in the PFC and an enhancement in HPC-PFC evoked responses. LTP induction prior to KET attenuates changes in synaptic efficiency and prevents the increase in cortical gamma amplitude comodulation. These findings are consistent with evidence that increased efficiency of glutamatergic receptors attenuates cognitive impairment in animal models of psychosis. Therefore, high-frequency stimulation in HPC may be a useful tool to better understand how to prevent NMDAr hypofunction effects on synaptic plasticity and oscillatory coordination in corticolimbic circuits. The hippocampal-prefrontal cortex (HPC-PFC) monosynaptic pathway is implicated in cognitive functions, such as working memory, decision making, and spatial-temporal processing 1,2. Dysfunctional connectivity within HPC-PFC circuits is associated with the pathophysiology and genetic predisposition to schizophrenia 3-5. In schizophrenia, HPC-PFC connectivity is decreased during working memory tasks and increased in resting state 5-7. Such effects may be mediated, at least in part, by N-methyl-D-aspartate receptor (NMDAr). NMDAr binding is reduced in schizophrenic patients in both HPC and PFC, and administration of an NMDAr antagonist, such as ketamine, can induce psychotic symptoms in healthy patients and an increase in resting-state HPC-PFC connectivity 8-10. This NMDAr hypofunction also affects synaptic plasticity, inducing impairments in critical circuits, such as HPC-PFC, promoting cognitive symptoms by pathological neural activity 11-13. However, the relationship between synaptic plasticity in HPC-PFC circuits and schizophrenia is not fully understood.

Neuromodulation of Hippocampal-Prefrontal Cortical Synaptic Plasticity and Functional Connectivity: Implications for Neuropsychiatric Disorders

“…In addition, we have recently shown that distinct coupling occurs between the HPC-mPFC during each state. In the deactivated state, we observed a coherence peak in the 0.5-2 Hz band, with the mPFC leading the HPC, while in the activated state, there was a peak in theta with the HPC leading the mPFC and a time lag consistent to data of freely-moving animals (Lopes-Aguiar et al, 2020). We also showed that mAChR activation by pilocarpine dose-dependently increased activated over deactivated states (Lopes-Aguiar et al, 2013).…”

“…While juvenile mice exhibited elevated cortical excitability in an uncoordinated manner relative to the HPC, adult mice showed weaker evoked potentials in mPFC and increased LTD, suggesting impaired functional connectivity during adulthood. In iHPC-mPFC, ketamine-induced aberrant oscillatory coupling in mPFC and alterations in the HPC-PFC synaptic efficacy ( Lopes-Aguiar et al, 2020 ). The authors demonstrated that prior induction of LTP in the CA1-mPFC attenuates these effects, highlighting the importance of high-frequency stimulation as a non-pharmacological alternative strategy to investigate HPC-PFC modulation and help in the prevention or attenuation of cognitive impairments in schizophrenia.…”

Network asynchrony underlying increased broadband gamma power

“…This pattern of gamma modulation is also observed under urethane anesthesia, which is characterized by cyclic alternations between cortical states that resemble NREM sleep oscillations (deactivated states) and REM sleep oscillations (activated states) (Clement et al, 2008). Systemic administration of ketamine alters the cyclic alternations between deactivated and activated states, and the coupling between delta and gamma oscillations in the mPFC in urethane anesthetized rats (Lopes-Aguiar et al, 2020). Importantly, PV inhibition is suggested to regulate state transitions (Zucca et al, 2017).…”

“…S1D, E). Urethane anesthesia is a validated model for testing of mechanistic hypotheses regarding sleep-like brain oscillations (Hauer et al, 2019), and has been particularly employed for investigation of the effects of NMDAR antagonists on oscillatory patterns in different brain circuits (Kiss et al, 2013;Lopes-Aguiar et al, 2020). Use of an anesthetized preparation circumvents the increases in gamma power associated with hyperlocomotion elicited by administration of NMDAR antagonists in awake mice (Hakami et al, 2009).…”

“…Increased spontaneous broadband gamma oscillations have also been demonstrated in other mouse models of PV neuron dysfunctions (del Pino et al, 2013;Cho et al, 2015), and in individuals with schizophrenia (Mathalon and Sohal, 2015;Grent-'t-Jong et al, 2018). Further, administration of NMDAR antagonists such as ketamine (Pinault, 2008;Hakami et al, 2009;Kulikova et al, 2012;Caixeta et al, 2013;Picard et al, 2019;Lopes-Aguiar et al, 2020;Mahdavi et al, 2020;McNally et al, 2020), or MK-801 (Carlén et al, 2012;Molina et al, 2014;Hudson et al, 2020), is associated with increased power in spontaneous broadband gamma oscillations in both anesthetized and awake rodents, and also in humans (Rivolta et al, 2015). Importantly, lack of NMDAR in PV neurons blunts this response (Carlén et al, 2012;Picard et al, 2019;Hudson et al, 2020), confirming that cortical PV interneurons are a central target of NMDAR antagonists.…”