Effect of Neonatal Treatment With the NMDA Receptor Antagonist, MK-801, During Different Temporal Windows of Postnatal Period in Adult Prefrontal Cortical and Hippocampal Function

Abstract

The neonatal MK-801 model of schizophrenia has been developed based on the neurodevelopmental and NMDA receptor hypofunction hypotheses of schizophrenia. This animal model is generated with the use of the NMDA receptor antagonist, MK-801, during different temporal windows of postnatal life of rodents leading to behavioral defects in adulthood. However, no studies have examined the role of specific postnatal time periods in the neonatal MK-801 (nMK-801) rodent model and the resulting behavioral and neurobiological effects. Thus, the goal of this study is to systematically investigate the role of NMDA hypofunction, during specific temporal windows in postnatal life on different cognitive and social behavioral paradigms, as well as various neurobiological effects during adulthood. Both female and male mice were injected intraperitoneally (i.p.) with MK-801 during postnatal days 7–14 (p7–14) or 11–15 (p11–15). Control mice were injected with saline during the respective time period. In adulthood, mice were tested in various cognitive and social behavioral tasks. Mice nMK-801-treated on p7–14 show impaired performance in the novel object, object-to-place, and temporal order object recognition (TOR) tasks, the sociability test, and contextual fear extinction. Mice nMK-801-treated on p11–15 only affects performance in the TOR task, the social memory test, and contextual fear extinction. No differences were identified in the expression of NMDA receptor subunits, the synapsin or PSD-95 proteins, either in the prefrontal cortex (PFC) or the hippocampus (HPC), brain regions significantly affected in schizophrenia. The number of parvalbumin (PV)-expressing cells is significantly reduced in the PFC, but not in the HPC, of nMK-801-treated mice on p7–14 compared to their controls. No differences in PV-expressing cells (PFC or HPC) were identified in nMK-801-treated mice on p11–15. We further examined PFC function by recording spontaneous activity in a solution that allows up state generation. We find that the frequency of up states is significantly reduced in both nMK-801-treated mice on p7–14 and p11–15 compared to saline-treated mice. Furthermore, we find adaptations in the gamma and high gamma activity in nMK-801-treated mice. In conclusion, our results show that MK-801 treatment during specific postnatal temporal windows has differential effects on cognitive and social behaviors, as well as on underlying neurobiological substrates.

The effects and mechanism of environmental enrichment on MK-801 induced cognitive impairment in rodents with schizophrenia

“…And the performance of male and female Wistar neonatal rats is similar (Faatehi et al, 2019). Treatment of C57BL/6 neonatal mice with low concentrations of MK-801, such as 0.1 mg/kg, has similar effects (Plataki et al, 2021). However, it has also been argued that chronic MK-801 administration induces working memory deficits in NOR with a threshold of administration concentration, and only concentrations higher than 0.5 mg/kg can successfully induce working memory deficits (Murueta-Goyena et al, 2018).…”

“…For example, C57BL/6 neonatal mice show impaired discrimination index when MK-801 is administered on postnatal days 7–14, but there is no significant difference in NOR results between MK-801 treated and control mice when MK-801 is administered on postnatal days 11–15. This suggests that there is a time window for the effect of MK-801 on cognitive function (Plataki et al, 2021 ). In addition, acute MK-801 treatment also reduces the discrimination index of male C57/BL6J mice (Prades et al, 2017 ).…”

Epigenetic Targets in Schizophrenia Development and Therapy

“…The early-life or adolescent blockade of NMDA receptors induced the schizophrenia-like behavioural response in adult animals [ 102 ]. Biochemical studies have shown that behavioural changes are related to the alterations in histone acetylation (H3K9ac) [ 103 ] or in HDAC5 levels in the adult PFC of animals with postnatal blockade of NMDA receptors [ 103 , 104 ].…”

Understanding the role of the NMDA receptor subunit, GluN2D, in mediating NMDA receptor antagonist‐induced behavioral disruptions in male and female mice

“…Multiple studies have shown that administration of sub‐anesthetic doses of ketamine and PCP can induce a spectrum of schizophrenia‐like symptoms including psychosis and neurocognitive disturbances in healthy individuals, and exacerbate symptoms in people with schizophrenia (Allen & Young, 1978; Cheng et al, 2018; Krystal et al, 1994; Lahti et al, 1995; Luby et al, 1959; Xu et al, 2015). In rodents, administration of these NMDAR channel blockers results in hyperlocomotion (proposed to represent a striatal hyperdopaminergic state which is thought to underlie the positive symptoms of schizophrenia like psychosis), disruption of the prepulse inhibition of the startle response, and cognitive deficits as assessed by various behavioral tests including the T‐maze and object recognition tasks (Cadinu et al, 2018; Gigg et al, 2020; Neill et al, 2014; Plataki et al, 2021; Sahin et al, 2016; Suryavanshi et al, 2014; Usun et al, 2013). Multiple studies have reported that GluN2D knockout (KO) mice are resistant to NMDAR antagonist‐induced hyperlocomotion, thus suggesting a role for the GluN2D subunit in mediating psychotomimetic drug‐induced hyperlocomotor behavior (Hagino et al, 2010; Ikeda et al, 1995; Sapkota et al, 2016; Yamamoto et al, 2016).…”