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Neurodevelopmental ATM deficiency affects glutamatergic transmission through KCC2-KARs expression in the hippocampus but not in the cortex

ABSTRACT: Interest in the function of ataxia-telangiectasia mutated protein (ATM) is extensively growing as evidenced by preclinical studies which continuously associate ATM loss with new intracellular pathways. To further investigate ATM involvement in neurotransmission, we initially exploited ATM+/- and ATM-/- mice. ATM defective animals display cognitive defects rescued by the delivery of the antidepressant Fluoxetine (Fluox). Prenatal Fluox increases levels of the chloride intruder NKCC1, previously described lowered in ATM defective mice. Surprisingly, this result occurs exclusively at hippocampal level suggesting an ATM context-specificity. Indeed, a deeper investigation of excitatory synapses revealed increased Gluk1 and Gluk5 subunit-containing kainate receptors (KARs) levels in the hippocampus, but not cortex, of ATM+/- and ATM-/- mice. The comparable composition between wt and ATM+/- post-synapses (TIF purification) suggests a presynaptic KARs localization and in vitro and in ex vivo electrophysiology that KARs are fully active. Since KAR subunits functionally interact with the chloride cotransporter KCC2, which is highly expressed in ATM deficient mice, we blocked KCC2 activity during the development of ATM+/- cultures and found reduced KARs levels. Conversely, the transient and acute blockade of ATM kinase activity achieved by KU55933 in adults does not move similar changes as indicated by a completely different panel of deregulated genes identified in RNA-seq investigation performed on hippocampi explanted from KU mice. Our data, indicating that such alterations are developmental regulated and linked to ATM kinase activity through the KCC2 regulation, add new findings useful for a deeper understanding of ATM function in central neurons. Importantly, controlling the KCC2/NKCC1 levels, ATM affects both the GABAergic and glutamatergic system in the hippocampus.

ORGANISM(S): Mus musculus

PROVIDER: GSE202217 | GEO | 2022/07/05

REPOSITORIES: GEO

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Project description:Body temperature is maintained in a narrow range in mammals, primarily controlled by sweating. In humans, the dynamic thermoregulatory organ, comprised of 2-4 million sweat glands distributed over the body, can secrete up to 4 liters of sweat per day1, thereby making it possible to withstand high temperatures and run long distances. The genetic basis for sweat gland function, however, is largely unknown. We find that a forkhead transcription factor, FoxA1, is required to generate mouse sweating capacity. When FoxA1 is ablated, mice are otherwise healthy and sweat gland morphogenesis occurs, but no sweating ensues, with the Nkcc1 sodium/potassium/chloride co-transporter and a specialized Ca2+-activated bicarbonate channel protein, Best2, both sharply down-regulated, and glycoprotein accumulating in gland lumens and ducts. Furthermore, Best2 knockout mice display comparable anhidrosis and glycoprotein accumulation. These findings link earlier observations that both sodium/potassium/chloride exchange and Ca2+ are required for sweat production. FoxA1 is inferred to regulate two corresponding features of sweat secretion. One, via Best2, catalyzes a bicarbonate gradient that could help to drive calcium-associated ionic transport; the other, requiring Nkcc1, facilitates monovalent ion exchange into sweat. These mechanistic components can be pharmaceutical targets to defend against hyperthermia and alleviate defective thermoregulation in the elderly2, and may provide a model relevant to more complex secretory processes. For expression profiling of FoxA1, hairless fore footpad skin (6) was collected from FoxA1 knockouts and wild-type littermates at P10, P14 and P31. Three skin samples from 3 embryos for each genotype at each time point were used for biological replicates. Total RNAs were isolated with Trizol (Invitrogen), precipitated by 7.5M LiCl (Ambion), and cyanine-3-labeled cRNAs were hybridized to the NIA Mouse 44K Microarray v3.0 (Agilent Technologies). Triplicate data were analyzed by ANOVA (6). Genes with FDR<0.05, fold difference>1.5 and mean log intensity>2.0 were considered to be significant.

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Neurodevelopmental ATM deficiency affects glutamatergic transmission through KCC2-KARs expression in the hippocampus but not in the cortex

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