Macrophage attenuation of neuronal excitability: implications for pathogenesis of neurodegenerative disorders

Brain macrophages (and microglia) play a crucial role in central nervous system immune and inflammatory responses. They are also critical cells in the pathogenesis of neurodegenerative disorders. To understand how macrophages cause neural cell dysfunction, we investigated the effects of mouse bone marrow-derived macrophages (BMDMs) on rat cortical neuronal physiology in a BMDM-neuronal co-culture system using whole-cell patch clamp techniques. When co-cultured with neuronal cells, BMDMs hyperpolarized the neuronal membrane and attenuated both spontaneous and electrically evoked firings through a decrease in membrane input resistance. The average duration of evoked action potentials (APs) and the latency to fire the APs, in response to a constant depolarizing current injection, were significantly increased by BMDMs. These results indicate that BMDMs attenuate neuronal excitability. Further investigation revealed that BMDMs hyperpolarize neuronal membranes by enhancing neuronal delayed rectifier potassium current (IK), which was blocked by tetraethylammonium. This BMDM-induced attenuation on neuronal excitability may contribute to the pathogenesis of neuronal dysfunction and damage as seen in neurodegenerative disorders.