Hippocampal synaptic dysfunction in the SOD1^G93A mouse model of Amyotrophic Lateral Sclerosis: Reversal by adenosine A_2AR blockade

Amyotrophic Lateral Sclerosis (ALS) mostly affects motor neurons, but non-motor neural and cognitive alterations have been reported in ALS mouse models and patients. Here, we evaluated if time-dependent biphasic changes in synaptic transmission and plasticity occur in hippocampal synapses of ALS SOD1^G93A mice. Recordings were performed in hippocampal slices of SOD1^G93A and age-matched WT mice, in the pre-symptomatic and symptomatic stages. We found an enhancement of pre-synaptic function and increased adenosine A_2A receptor levels in the hippocampus of pre-symptomatic mice. In contrast, in symptomatic mice, there was an impairment of long-term potentiation (LTP) and a decrease in NMDA receptor-mediated synaptic currents, with A_2AR levels also being increased. Chronic treatment with the A_2AR antagonist KW-6002, rescued LTP and A_2AR values. Altogether, these findings suggest an increase in synaptic function during the pre-symptomatic stage, followed by a decrease in synaptic plasticity in the symptomatic stage, which involves over-activation of A_2AR from early disease stages.