One of the challenges for space exploration is the exposition of astronauts to gravitational intensity changes that could affect crew performance through sensory systems and cognition deterioration. This preclinical study aimed at investigating functional synaptic changes in hippocampal neuronal networks to hypergravity (HG) that could manage cognitive impairments. Male and female mice were exposed to a 24h, 48h or 15 days exposure to 2G. Synaptic activity was then assessed by electrophysiological recordings in the hippocampal CA1 area from ex vivo slice preparations. In male mice, long-term potentiation (LTP) of synaptic strength induced by high-frequency stimulation and NMDA receptor (NMDAr) activation driving LTP were impaired after 24h but not 48h or 15-day exposure. Both deficits were prevented by delivering D-serine to slices indicating a weaker activation of the NMDAr co-agonist binding site. In female mice, LTP induced by theta burst stimulation and NMDAr activation were reduced but only after 15-day exposure. This deficit could only partially compensated by D-serine addition. This result suggests that LTP and NMDAR activation deficits do not fully rely on a weaker synaptic availability of endogenous D-serine. This electrophysiological study emphasizes sex-dependent changes in functional plasticity in CA1 hippocampal networks of mice exposed to HG. Evidence is provided for sex differences in CA1 hippocampal networks that rely not only on time exposure to HG but also on the form of LTP and on the underlying synaptic mechanisms. Whether these sex-dependent changes in functionality may trigger significant cognitive deficits is currently under investigation.