Summary: New research implicates an altered balance between two chloride transporters—NKCC1 and KCC2—as a key contributor to cognitive deficits in schizophrenia. In mouse models, blocking NKCC1 with the FDA-approved diuretic bumetanide restored inhibitory GABAA signaling and rescued performance on multiple cognitive tests.
Source: Northwestern University
Altered chloride transport and a shift in GABAA current polarity may underlie cognitive deficits in schizophrenia, according to a Northwestern Medicine study published in Science Advances.
The study shows that changes in the relative levels of the chloride transporters NKCC1 and KCC2 can make the normally inhibitory GABAA current become excitatory. In adult mice modeling cognitive symptoms of schizophrenia, this depolarizing switch was linked to impaired cognition. Pharmacologically inhibiting NKCC1 with bumetanide, a drug already approved for human use as a diuretic, restored inhibitory GABAA signaling and improved cognitive performance in these animals.
“To our surprise, it completely reversed deficits on three different tests of cognitive performance,” said Marco Martina, MD, MSc, PhD, associate professor of Physiology and the study’s senior author.
Herbert Meltzer, MD, professor of Psychiatry and Behavioral Sciences, Pharmacology and Physiology, is listed as a co-author on the paper.
GABAA-mediated currents provide the main inhibitory drive in the adult brain and are essential for maintaining the balance between excitation and inhibition alongside excitatory signals such as glutamate. During early development—up to around two years of age in humans—GABAA currents are depolarizing and act excitatorily. The direction (polarity) of GABAA currents depends on intracellular chloride concentration, which is regulated by the opposing actions of NKCC1 (which imports chloride) and KCC2 (which exports chloride).
Early in development NKCC1 dominates, raising intracellular chloride and rendering GABAA excitation. As KCC2 expression increases during maturation, intracellular chloride falls and GABAA signaling becomes inhibitory. The Northwestern team found that, in a mouse model relevant to cognitive impairment in schizophrenia (subchronic phencyclidine, scPCP), the balance between these transporters was altered in adulthood: NKCC1 expression was abnormally high in a localized region of the prefrontal cortex, leading to a depolarizing GABAA current in pyramidal neurons.
Prior research into GABAA’s role in schizophrenia-related cognitive symptoms produced mixed results—some studies suggested increased GABA signaling, others decreased. Martina noted that few studies had examined the possibility that GABAA itself becomes depolarizing in adult disease states. The current work directly tested that hypothesis and identified a clear mechanistic link between depolarizing GABAA currents and cognitive impairment in the scPCP model.
Treating the scPCP mice with bumetanide, an NKCC1 antagonist, normalized the polarity of GABAA currents when measured ex vivo and led to marked improvements in several cognitive tasks when tested in vivo. A complementary approach—using a viral construct to selectively knock down NKCC1 expression in the infralimbic region of the prefrontal cortex—produced similar behavioral improvements, supporting a causal role for NKCC1 upregulation in the observed cognitive deficits.
The study highlights why chloride transporters are uniquely capable of shifting neural polarity: unlike sodium or potassium channels, whose equilibrium potentials sit far from resting membrane potential and are therefore relatively insensitive to moderate concentration changes, chloride-dependent signaling is programmed to invert during normal development. That built-in flexibility makes chloride homeostasis particularly vulnerable—small pathological perturbations can flip the sign of GABAA-mediated currents and disrupt neural network function.
“Most biological systems have redundancy, but chloride channels are designed to change at a specified developmental stage,” Martina explained. “Any disturbance in that process can affect whether GABAA signaling is inhibitory or excitatory.”
Martina and colleagues also noted that this mechanism could apply to other disorders that feature cognitive deficits. They plan to investigate whether altered GABAA polarity contributes to conditions such as autism spectrum disorders and other neurodevelopmental or neuropsychiatric illnesses.
Co-lead authors on the paper were Haram Kim, PhD, a postdoctoral fellow in the Martina laboratory, and Lakshmi Rajagopal, PhD, a postdoctoral fellow in the Meltzer laboratory.
Funding: This research was supported by National Institutes of Health grants DA044121, NS112292, and MH109466, and by a donation from the Weisman family.
About this schizophrenia research news
Source: Northwestern University
Contact: Will Doss – Northwestern University
Image: The image is credited to the researchers
Original Research: Open access. “Depolarizing GABAA current in the prefrontal cortex is linked with cognitive impairment in a mouse model relevant for schizophrenia” by Marco Martina et al., Science Advances.
Abstract
Depolarizing GABAA current in the prefrontal cortex is linked with cognitive impairment in a mouse model relevant for schizophrenia
Cognitive impairment in schizophrenia (CIAS) strongly predicts functional outcome, but progress in developing effective treatments has been limited by incomplete understanding of its cellular mechanisms. In subchronic phencyclidine (scPCP)–treated mice, a model that reproduces aspects of CIAS, the reversal potential of GABAA currents in pyramidal neurons of the infralimbic prefrontal cortex shifts from hyperpolarizing to depolarizing due to elevated NKCC1 expression.
In these mice, the NKCC1 antagonist bumetanide restored GABAA current polarity in slice recordings and improved cognitive performance across multiple behavioral tasks in vivo. Selective bilateral knockdown of NKCC1 in the infralimbic cortex replicated the behavioral rescue, indicating that depolarizing GABAA currents in this region contribute to the cognitive deficits observed in the scPCP model. These findings suggest that targeting NKCC1 with agents such as bumetanide could have potential to treat or prevent aspects of cognitive impairment associated with schizophrenia.