Ketamine-Treatment During Late Adolescence Impairs Inhibitory Synaptic Transmission in the Prefrontal Cortex and Working Memory in Adult Rats

Abstract

Schizophrenia (SZ) is associated with changes in the structure and function of several brain areas. Several findings suggest that these impairments are related to a dysfunction in γ-aminobutyric acid (GABA) neurotransmission in brain areas such as the medial prefrontal cortex (mPFC), the hippocampus (HPC) and the primary auditory cortex (A1); however, it is still unclear how the GABAergic system is disrupted in these brain areas. Here, we examined the effect of ketamine (Ket) administration during late adolescence in rats on inhibition in the mPFC-, ventral HPC (vHPC), and A1. We observe that Ket treatment reduced the expression of the calcium-binding protein parvalbumin (PV) and the GABA-producing enzyme glutamic acid decarboxylase 67 (GAD67) as well as decreased inhibitory synaptic efficacy in the mPFC. In addition, Ket-treated rats performed worse in executive tasks that depend on the integrity and proper functioning of the mPFC. Conversely, we do not find such changes in vHPC or A1. Together, our results provide strong experimental support for the hypothesis that during adolescence, the function of the mPFC is more susceptible than that of HPC or A1 to NMDAR hypofunction, showing apparent structure specificity. Thus, the impairment of inhibitory circuitry in mPFC could be a convergent primary site of SZ-like behavior during the adulthood.

Behavioral Consequences of a Combination of Gad1 Haplodeficiency and Adolescent Exposure to an NMDA Receptor Antagonist in Long-Evans Rats

“…In the present study, MK-801 treatment also reduced the time spent in the open arms, although the effect was at a subthreshold level ( p = 0.055). This result suggests that chronic MK-801 treatment during adolescence may alter anxiety levels, as reported previously ( Uttl et al, 2018 ; Pérez et al, 2019 ). Consequently, the decision-making process may be affected by the altered anxiety level.…”

“…The most bizarre phenomenon observed in the present study was the absence of the MK-801-induced reduction in social novelty preference in HET rats. The blockade of NMDA receptors during adolescence impairs social novelty preference in mice ( Pérez et al, 2019 ). Such changes in social behavior are thought to be associated with reductions in GAD67 and PV neurons in the prefrontal cortex ( Pérez et al, 2019 ).…”

“…The blockade of NMDA receptors during adolescence impairs social novelty preference in mice ( Pérez et al, 2019 ). Such changes in social behavior are thought to be associated with reductions in GAD67 and PV neurons in the prefrontal cortex ( Pérez et al, 2019 ). The reason why the HET rats were resistant to the effect of MK-801 in terms of social novelty preference can be explained as follows: the secondary changes caused by congenital Gad1 haplodeficiency showed a defensive effect against MK-801.…”

“…For instance, the administration of phencyclidine, an antagonist of the NMDA-type glutamate receptor, induces a wide range of schizophrenic symptoms in humans and rodent models ( Lee and Zhou, 2019 ). Other NMDA receptor antagonists, such as ketamine and MK-801, have similar effects and are frequently used to establish a pharmacological model of schizophrenia ( Kawabe et al, 2007 ; Kawabe, 2017 ; Unal et al, 2018 ; Pérez et al, 2019 ). Since the most susceptible age for the disorder is from adolescence to young adulthood, chronic pharmacological blockade of NMDA during this period is a possible model for schizophrenia.…”

“…Since the most susceptible age for the disorder is from adolescence to young adulthood, chronic pharmacological blockade of NMDA during this period is a possible model for schizophrenia. Such animal models show impaired spatial cognition ( Rujescu et al, 2006 ; Li et al, 2016 ), enhanced anxiety-like behaviors ( Uttl et al, 2018 ; Pérez et al, 2019 ), decreased social novelty preference ( Pérez et al, 2019 ), and impaired prepulse inhibition ( Ma et al, 2020 ). The molecular details underpinning these behavioral alterations are still unclear.…”