Astrocyte-mediated transduction of muscle fiber contractions synchronizes hippocampal neuronal network development

Abstract

Exercise supports brain health in part through enhancing hippocampal function. The leading hypothesis is that muscles release factors when they contract (e.g., lactate, myokines, growth factors) that enter circulation and reach the brain where they enhance plasticity (e.g., increase neurogenesis and synaptogenesis). However, it remains unknown how the muscle signals are transduced by the hippocampal cells to modulate network activity and synaptic development. Thus, we established an in vitro model in which the media from contracting primary muscle cells (CM) is applied to developing primary hippocampal cell cultures on a microelectrode array. We found that the hippocampal neuronal network matures more rapidly (as indicated by synapse development and synchronous neuronal activity) when exposed to CM than regular media (RM). This was accompanied by a fourfold increase in the proliferation of astrocytes. Further, experiments established that the astrocytes release factors that inhibit neuronal excitability and facilitate network development. Results provide new insight into how exercise may support hippocampal function through regulating astrocyte proliferation and subsequent taming of neuronal activity into an integrated network.