Adenosine deficiency facilitates CA1 synaptic hyperexcitability in the presymptomatic phase of a knock in mouse model of Alzheimer's disease.

Abstract

The diseases trajectory of Alzheimers disease (AD) is associated with and worsened by hippocampal hyperexcitability. Here we show that during the asymptomatic stage in a knock in mouse model of Alzheimers 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 Alzheimers 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 Alzheimers disease. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=181 SRC="FIGDIR/small/590882v1_ufig1.gif" ALT="Figure 1"> View larger version (39K): org.highwire.dtl.DTLVardef@cd128forg.highwire.dtl.DTLVardef@17d7701org.highwire.dtl.DTLVardef@100337org.highwire.dtl.DTLVardef@14333d0_HPS_FORMAT_FIGEXP M_FIG C_FIG O_LISynaptic hyperexcitability spreads to the soma and manifests at low frequencies of stimulation C_LIO_LISynaptic hyperexcitability is associated with reduced adenosine tone in vitro and in vivo C_LIO_LIReduced adenosine tone is driven by reduced ATP-to-adenosine extracellular conversion C_LIO_LIRestoration of adenosine tone successfully normalizes neuronal excitability in the AD model C_LI