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

Abstract

<jats:title>ABSTRACT</jats:title><jats:p>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 with schizophrenia, particularly in the hippocampus and the prefrontal cortex. In contrast, long-term potentiation (LTP) induction is known to increase glutamatergic transmission. Thus, we hypothesized that 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 crossfrequency 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 cortico-limbic circuits.</jats:p>

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.…”