Depolarizing GABA _A current in the prefrontal cortex is linked with cognitive impairment in a mouse model relevant for schizophrenia

Abstract

Cognitive impairment in schizophrenia (CIAS) is the most critical predictor of functional outcome. Limited understanding of the cellular mechanisms of CIAS hampers development of more effective treatments. We found that in subchronic phencyclidine (scPCP)–treated mice, an animal model that mimics CIAS, the reversal potential of GABAA currents in pyramidal neurons of the infralimbic prefrontal cortex (ILC) shifts from hyperpolarizing to depolarizing, the result of increased expression of the chloride transporter NKCC1. Further, we found that in scPCP mice, the NKCC1 antagonist bumetanide normalizes GABAA current polarity ex vivo and improves performance in multiple cognitive tasks in vivo. This behavioral effect was mimicked by selective, bilateral, NKCC1 knockdown in the ILC. Thus, we show that depolarizing GABAA currents in the ILC contributes to cognitive impairments in scPCP mice and suggest that bumetanide, an FDA-approved drug, has potential to treat or prevent CIAS and other components of the schizophrenia syndrome.

Differential Rearrangement of Excitatory Inputs to the Medial Prefrontal Cortex in Chronic Pain Models

“…The altered synaptic inputs may also cause a more general effect, which is a widespread alteration of the excitation/inhibition (E/I) balance. E/I imbalance is regarded as a key pathogenic mechanism in numerous neurodevelopmental disorders (Deidda et al, 2015;Kim et al, 2021). Thus, it is possible that through recurrent inhibitory and excitatory circuitries the mPFC network acts as a magnifier of the effects of even minor alterations in specific inputs, so that relatively minor synaptic changes end up producing large behavioral effects.…”

Dysregulation of GABAergic Signaling in Neurodevelomental Disorders: Targeting Cation-Chloride Co-transporters to Re-establish a Proper E/I Balance

“…In the subchronic phencyclidine (scPCP)-treated mice, a well-studied animal model mimicking the cognitive impairment symptoms associated with schizophrenia (Jentsch and Roth, 1999 ; Steeds et al, 2015 ; Kim et al, 2021 ) found that the reversal potential of GABA (E GABA ) recorded from pyramidal neurons in the infralimbic cortex (the more ventral portion of the prefrontal cortex) was more positive in scPCP-treated mice as compared to those treated with vehicle. This effect was highly specific since it was not found in the prelimbic cortex, which is also part of the prefrontal cortex and sits just above the infralimbic cortex.…”

Pharmacological tools to target NKCC1 in brain disorders

“…Thus, recent investigations hypothesized that bumetanide levels in the brain after systemic administration were not sufficient to cause NKCC1 inhibition, calling into question whether brain-expressed NKCC1 is the effector of the action of bumetanide in neurological disorders [117,118] (see Outstanding questions). However, RNAi-based experiments with downregulation of endogenous NKCC1 led to rescue of core symptoms in rodent models of four diverse neurological conditions, validating NKCC1 as a factual effector and, thus, as a pharmacological target in brain diseases [8][9][10][11][12]. In addition, despite its low brain penetration, bumetanide efficacy should be assessed by taking into consideration the low [Cl -] i variations (and so a likely low level of NKCC1 inhibition) necessary to affect neuronal excitability [119] (Box 1).…”

“…Several NDs are characterized by cognitive impairment (deficits in memory, attention, and cognitive flexibility), including DS (a genetic disorder caused by triplication of chromosome 21), schizophrenia (a psychiatric disorder the cause of which is not completely understood), and fetal alcohol spectrum disorders (FASD) (a group of conditions caused by prenatal alcohol exposure). NKCC1 upregulation was reported in adult Ts65Dn mice, a model of DS [39], and in scPCP mice, a model of schizophrenia [8] (Table 1). Bumetanide ameliorated cognitive impairments in these two models [8,39] (Table 2).…”

“…NKCC1 upregulation was reported in adult Ts65Dn mice, a model of DS [39], and in scPCP mice, a model of schizophrenia [8] (Table 1). Bumetanide ameliorated cognitive impairments in these two models [8,39] (Table 2). Both NKCC1 upregulation and KCC2 downregulation were found in dysbindin mutant mice, another model of schizophrenia [40].…”