Saturday, September 7, 2024
9/7/2024
Summary Excitation/inhibition imbalance is considered a major factor leading to cognitive impairment and social interaction deficits in neurodevelopmental disorders (e.g. schizophrenia), yet the cellular mechanisms underlying this imbalance are not fully established. Using subchronic phencyclidine (scPCP)-treated mice, a pharmacological model of cognitive impairment associated with schizophrenia, we discovered that GABAA function shifts from inhibitory to excitatory in pyramidal neurons of the medial prefrontal cortex of scPCP mice. We further found that this shift is caused by the selective enhancement of the expression of the chloride transporter NKCC1, and that NKCC1 antagonism using the NKKC1 inhibitor bumetanide completely restores the GABAA current reversal potential to the control values. Importantly, we also showed that in-vivo treatment with bumetanide (IP or local cortical infusion) rescues cognitive performance in scPCP mice. Our preliminary data further validate these results, showing that bumetanide rescues cognitive performance in male 16p11.2 duplication mice, a genetic model relevant for schizophrenia. We hypothesize that depolarizing GABAA signaling in the mPFC represents a convergent pathogenic mechanism causing impaired cognition across multiple genetic models relevant to schizophrenia and that bumetanide treatment may be effective across all these models. To test this hypothesis, we will take advantage of three etiologically different genetic mouse models reflecting variable genetic risk for schizophrenia: a copy number variant model (16p11.2 duplication), a rare variants model (TRIO+/-), and a common variant model (Cacna1C+/-). These models were developed to mimic genetic conditions known to significantly increase the incidence of psychiatric disorders including schizophrenia in humans and show numerous deficits in PFC-specific cognitive tasks such as working memory and reversal learning. In Aim 1 we will use perforated patch recordings in acute cortical slices to determine the reversal potential of the GABAA current in pyramidal cells of the mPFC, and quantitative in situ hybridization to quantify expression of NKCC1 and KCC2 transcripts in mPFC from male and female mice. In Aim 2 we will use behavioral assessment of wild-type mice in which mPFC NKCC1/KCC2 is increased using pharmacologic or genetic tools to test the hypothesis that increased mPFC NKCC1/KCC2 is a condition sufficient to cause cognitive impairment, even in the absence of other cellular dysfunctions. We will also the effects of this manipulation on mPFC gene expression and morphology. Finally, in Aim 3, we will determine the behavioral effects of NKCC1 inhibition in our three disease models. We will test the effects of acute and chronic treatment with bumetanide, as well as of selective genetic alteration of the NKCC1/KCC2 ratio in the mPFC of these mice, on several cognitive tests. We will also test the alternative hypothesis that bumetanide acts on glia rather than neuronal cells. Successful completion of our experiments may have important translational relevance as bumetanide is an FDA-approved drug and thus could be immediately tested in clinical trials.
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