ABSTRACT
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 SOD1G93A mice. Recordings were performed in hippocampal slices of SOD1G93A and age-matched WT mice, in the pre-symptomatic and symptomatic stages. We found an enhancement of pre-synaptic function and increased adenosine A2A 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 A2AR levels also being increased. Chronic treatment with the A2AR antagonist KW-6002, rescued LTP and A2AR 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 A2AR from early disease stages.
Subject(s)
Adenosine A2 Receptor Antagonists/therapeutic use , Amyotrophic Lateral Sclerosis/pathology , Hippocampus/drug effects , Hippocampus/pathology , Receptor, Adenosine A2A/drug effects , Superoxide Dismutase-1/genetics , Synapses/drug effects , Synapses/pathology , Amyotrophic Lateral Sclerosis/genetics , Animals , Excitatory Postsynaptic Potentials/drug effects , Humans , Long-Term Potentiation/drug effects , Mice , Mice, Transgenic , Neuronal Plasticity/drug effects , Purines/therapeutic use , Receptors, N-Methyl-D-Aspartate/drug effects , Synaptic Transmission/drug effectsABSTRACT
Different forms of plasticity occur concomitantly in the nervous system. Whereas homeostatic plasticity monitors and maintains neuronal activity within a functional range, Hebbian changes such as long-term potentiation (LTP) modify the relative strength of specific synapses after discrete changes in activity and are thought to provide the cellular basis for learning and memory. Here, we assessed whether homeostatic plasticity could influence subsequent LTP in acute hippocampal slices that had been briefly deprived of activity by blocking action potential generation and N-methyl-D-aspartate (NMDA) receptor activation for 3 h. Activity deprivation enhanced the frequency and the amplitude of spontaneous miniature excitatory postsynaptic currents and enhanced basal synaptic transmission in the absence of significant changes in intrinsic excitability. Changes in the threshold for Hebbian plasticity were evaluated by inducing LTP with stimulation protocols of increasing strength. We found that activity-deprived slices consistently showed higher LTP magnitude compared with control conditions even when using subthreshold theta-burst stimulation. Enhanced LTP in activity-deprived slices was also observed when picrotoxin was used to prevent the modulation of GABAergic transmission. Finally, we observed that consecutive LTP inductions attained a higher magnitude of facilitation in activity-deprived slices, suggesting that the homeostatic plasticity mechanisms triggered by a brief period of neuronal silencing can both lower the threshold and raise the ceiling for Hebbian modifications. We conclude that even brief periods of altered activity are able to shape subsequent synaptic transmission and Hebbian plasticity in fully developed hippocampal circuits.
