Short-Term Exposure to Enriched Environment in Adult Rats Restores MK-801-Induced Cognitive Deficits and GABAergic Interneuron Immunoreactivity Loss

Abstract

Perinatal injections of N-methyl-D-aspartate (NMDA) receptor antagonist in rodents emulate some cognitive impairments and neurochemical alterations, such as decreased GABAergic (gamma aminobutyric acid) interneuron immunoreactivity, also found in schizophrenia. These features are pervasive, and developing neuroprotective or neurorestorative strategies is of special interest. In this work, we aimed to investigate if a short exposure to enriched environment (EE) in early adulthood (P55-P73) was an effective strategy to improve cognitive dysfunction and to restore interneuron expression in medial prefrontal cortex (mPFC) and hippocampus (HPC). For that purpose, we administered MK-801 intraperitoneally to Long Evans rats from postnatal days 10 to 20. Twenty-four hours after the last injection, MK-801 produced a transient decrease in spontaneous motor activity and exploration, but those abnormalities were absent at P24 and P55. The open field test on P73 manifested that EE reduced anxiety-like behavior. In addition, MK-801-treated rats showed cognitive impairment in novel object recognition test that was reversed by EE. We quantified different interneuron populations based on their calcium-binding protein expression (parvalbumin, calretinin, and calbindin), glutamic acid decarboxylase 67, and neuronal nuclei-positive cells by means of unbiased stereology and found that EE enhanced interneuron immunoreactivity up to normal values in MK-801-treated rats. Our results demonstrate that a timely intervention with EE is a powerful tool to reverse long-lasting changes in cognition and neurochemical markers of interneurons in an animal model of schizophrenia.

Low-concentration sevoflurane inhalation in treating MK801-induced schizophrenia like disease in mice and a feasibility study of schizophrenia patients

“…In summary, present study further substantiated the nding that MK801 administration to neonatal mice could induce a negative model of schizophrenia 43,44,45 . Speci cally 22,23,31 , a consecutive 5-day administration protocol of MK801 in neonatal mice (P7) induced negative symptoms of schizophrenia including hypoactivity and less sociability.…”

Effects of iTBS-rTMS on the Behavioral Phenotype of a Rat Model of Maternal Immune Activation

“…Like others, our study confirms that MIA offspring are primarily impaired in behavior requiring attentional decision as with PPI and NOR. Canetta et al (2016) and Wallace et al (2014) demonstrated MIA offspring being deficient in attentional set shifting and reversal learning (Wallace et al, 2014) but no signs of deficits in working memory were evident (Canetta et al, 2016;Nakamura et al, 2021), the latter being in accordance with the lack of deficits we found with MWM test. Canetta et al (2016) further demonstrated an impaired GABAergic transmission in the mPFC of adult MIA offspring which was selective for PV-expressing interneurons.…”

“…This impression is supported by the findings of Kentner et al (2016) and Zhao et al (2020), demonstrating that housing MIA offspring in an enriched environment (EE) reverses the cognitive deficits in spatial discrimination and the down-regulation of genes critical to synaptic transmission and plasticity. Similarly, rodent studies using NMDA receptor antagonist dizolcilpine (MK-801) injection to induce a schizophrenia-like state demonstrated beneficial effects of EE, reversing the MK-801 induced deficits in NOR and PPI (Murueta-Goyena et al, 2018;Huang et al, 2021), accompanied by recovery of PV immunoreactivity. Interestingly, the same effect could be achieved by selective chemogenetic activation of PV-expressing interneurons within frontal association cortex (Huang et al, 2021).…”

Maturational Changes in Prefrontal and Amygdala Circuits in Adolescence: Implications for Understanding Fear Inhibition during a Vulnerable Period of Development

“…This enduring effect in adult rats after peri-adolescent NMDA receptor disruption was reversed by increasing local GABAergic transmission in the PFC with a single local infusion of the GABAA positive allosteric modulator Indiplon. Evidence suggests that earlier disruption of NMDA signalling (via ketamine or MK-801 during the second-third postnatal week) has similar long-term effects in adulthood, reducing expression of PV, disrupting synaptic properties in interneurons, and causing disinhibition of pyramidal cells [72,73]. Taken together, these findings demonstrate (1) that GABAergic control of prefrontal excitability increases across development before reaching mature functional capacity in late adolescence, and (2) that sustained NMDA receptor transmission is critical for moderating the normal functional development of GABAergic inhibitory networks in the mPFC.…”