title: New Role of ATM in Controlling GABAergic Tone During Development.
abstract: The capacity to guarantee the proper excitatory/inhibitory balance is one of the most critical steps during early development responsible for the correct brain organization, function, and plasticity. GABAergic neurons guide this process leading to the right structural organization, brain circuitry, and neuronal firing. Here, we identified the ataxia telangiectasia mutated (ATM), a serine/threonine protein kinase linked to DNA damage response, as crucial in regulating neurotransmission. We found that reduced levels of ATM in the hippocampal neuronal cultures produce an excitatory/inhibitory unbalance toward inhibition as indicated by the higher frequency of miniature inhibitory postsynaptic current events and an increased number of GABAergic synapses. In vivo, the increased inhibition still persists and, even if a higher excitation is also present, a reduced neuronal excitability is found as indicated by the lower action potential frequency generated in response to high-current intensity stimuli. Finally, we found an elevated extracellular signal-regulated kinase 1/2 (ERK1/2) phosphorylation in heterozygous hippocampi associated with lower expression levels of the ERK1/2 phosphatase PP1. Given that the neurodegenerative condition associated with genetic mutations in the Atm gene, ataxia telangiectasia, presents a variable phenotype with impairment in cognition, our molecular findings provide a logical frame for a more clear comprehension of cognitive defects in the pathology, opening to novel therapeutic strategies.
authors.affiliation: Department of Biology and Biotechnology, Lazzaro Spallanzani, University of Pavia, 27100 Pavia, Italy Department of Biotechnology and Translational Medicine, University of Milan, 20129 Milan, Italy.
authors.forename: Lara
authors.initials: L
authors.lastname: Pizzamiglio
authors.affiliation: Department of Biotechnology and Translational Medicine, University of Milan, 20129 Milan, Italy Humanitas Clinical and Research Center, IRCCS Rozzano, Rozzano (Milan), Italy.
authors.forename: Elisa
authors.initials: E
authors.lastname: Focchi
authors.affiliation: Institute of Neuroscience, C.N.R., 20129 Milan, Italy.
authors.forename: Luca
authors.initials: L
authors.lastname: Murru
authors.affiliation: Department of Biotechnology and Translational Medicine, University of Milan, 20129 Milan, Italy.
authors.forename: Matteo
authors.initials: M
authors.lastname: Tamborini
authors.affiliation: Institute of Neuroscience, C.N.R., 20129 Milan, Italy.
authors.forename: Maria
authors.initials: M
authors.lastname: Passafaro
authors.affiliation: Humanitas Clinical and Research Center, IRCCS Rozzano, Rozzano (Milan), Italy Institute of Neuroscience, C.N.R., 20129 Milan, Italy.
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Menna
authors.affiliation: Humanitas Clinical and Research Center, IRCCS Rozzano, Rozzano (Milan), Italy Institute of Neuroscience, C.N.R., 20129 Milan, Italy.
authors.forename: Michela
authors.initials: M
authors.lastname: Matteoli
authors.affiliation: Department of Biotechnology and Translational Medicine, University of Milan, 20129 Milan, Italy Institute of Neuroscience, C.N.R., 20129 Milan, Italy.
authors.forename: Flavia
authors.initials: F
authors.lastname: Antonucci
mesh_terms: D000818:Animals; D064007:Ataxia Telangiectasia Mutated Proteins / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006624:Hippocampus / Q000166:cytology / Q000196:embryology / Q000378:metabolism*; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009433:Neural Inhibition / Q000502:physiology; D009474:Neurons / Q000166:cytology / Q000378:metabolism*; D010766:Phosphorylation; D027981:Symporters / Q000378:metabolism; D009435:Synaptic Transmission / Q000502:physiology*; D046509:Tissue Culture Techniques; D005680:gamma-Aminobutyric Acid / Q000008:administration & dosage / Q000378:metabolism*; D000096922:K Cl- Cotransporters
chemical_list: D064007:Ataxia Telangiectasia Mutated Proteins; D048049:Extracellular Signal-Regulated MAP Kinases; D027981:Symporters; D005680:gamma-Aminobutyric Acid; D000096922:K Cl- Cotransporters; C576325:Atm protein, mouse
keywords: ATM; KCC2; hippocampus; kinase–phosphatase cycle