Adenosine deficiency facilitates CA1 synaptic hyperexcitability in the presymptomatic phase of a knockin mouse model of Alzheimer disease

• Published in: iScience 2025-01, Vol.28 (1), p.111616, Article 111616
• Main Authors: Bonzanni, Mattia, Braga, Alice, Saito, Takashi, Saido, Takaomi C., Tesco, Giuseppina, Haydon, Philip G.
• Format: Article
• Language: English
• Subjects: Biological sciences; Molecular neuroscience; Neuroscience
• ISSN: 2589-0042; 2589-0042
• DOI: 10.1016/j.isci.2024.111616

The disease’s trajectory of Alzheimer disease (AD) is associated with and negatively correlated to hippocampal hyperexcitability. Here, we show that during the asymptomatic stage in a knockin (KI) mouse model of Alzheimer disease (APPNL−G-F/NL−G-F; APPKI), hippocampal hyperactivity occurs at the synaptic compartment, propagates to the soma, and is manifesting at low frequencies of stimulation. We show that this aberrant excitability is associated with a deficient adenosine tone, an inhibitory neuromodulator, driven by reduced levels of CD39/73 enzymes, responsible for the extracellular ATP-to-adenosine conversion. Both pharmacologic (adenosine kinase inhibitor) and non-pharmacologic (ketogenic diet) restorations of the adenosine tone successfully normalize hippocampal neuronal activity. Our results demonstrated that neuronal hyperexcitability during the asymptomatic stage of a KI model of Alzheimer disease originated at the synaptic compartment and is associated with adenosine deficient tone. These results extend our comprehension of the hippocampal vulnerability associated with the asymptomatic stage of Alzheimer disease. [Display omitted] •Synaptic hyperexcitability spreads to the soma at low frequencies of stimulation•Reduced adenosine tone facilitates synaptic hyperexcitability in vitro and in vivo•ATP-to-adenosine extracellular conversion drives reduced adenosine tone•Restoring adenosine tone normalizes neuronal excitability in the AD model Biological sciences; Neuroscience; Molecular neuroscience