Pizzamiglio Lara, Focchi Elisa, Murru Luca, Tamborini Matteo, Passafaro Maria, Menna Elisabetta, Matteoli Michela, Antonucci Flavia
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.
Department of Biotechnology and Translational Medicine, University of Milan, 20129 Milan, Italy Humanitas Clinical and Research Center, IRCCS Rozzano, Rozzano (Milan), Italy.
Cereb Cortex. 2016 Oct;26(10):3879-88. doi: 10.1093/cercor/bhw125. Epub 2016 May 10.
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.
保证适当的兴奋/抑制平衡的能力是早期发育过程中最关键的步骤之一，负责正确的大脑组织、功能和可塑性。γ-氨基丁酸能神经元引导这一过程，从而实现正确的结构组织、脑回路和神经元放电。在此，我们确定了共济失调毛细血管扩张症突变基因（ATM），一种与DNA损伤反应相关的丝氨酸/苏氨酸蛋白激酶，在调节神经传递中起关键作用。我们发现，海马神经元培养物中ATM水平的降低会导致兴奋/抑制平衡向抑制方向失衡，表现为微小抑制性突触后电流事件的频率更高以及γ-氨基丁酸能突触数量增加。在体内，抑制增强仍然存在，并且即使也存在更高的兴奋性，响应高电流强度刺激产生的动作电位频率降低也表明神经元兴奋性降低。最后，我们发现杂合海马中细胞外信号调节激酶1/2（ERK1/2）的磷酸化升高，这与ERK1/2磷酸酶PP1的表达水平降低有关。鉴于与Atm基因突变相关的神经退行性疾病共济失调毛细血管扩张症表现出认知受损的可变表型，我们的分子研究结果为更清晰地理解该病理学中的认知缺陷提供了一个逻辑框架，为新的治疗策略开辟了道路。
