Morphological and functional differences between hippocampal and cortical microglia and its impact on neuronal over-excitation in a germline Pten mutant mouse model

Abstract

High-throughput, transcriptomic analyses of the brain have revealed significant differences of microglia between the hippocampus and the cortex. However, it remains unclear whether these regional differences translate into different microglial behaviors and impact disease progression. Here, we show that microglia possess higher morphological complexity and phagocytic capacity in the hippocampus compared to the cortex of wild-type mice. These regional differences are preserved in mice harboring a germline Pten mutation, which have a general increase of microglial ramification and phagocytic capacity. Moreover, we find that Pten-mutant microglia protect neurons from over-excitation through pruning excessive excitatory synapses and forming more microglia-neuron junctions. However, Pten-mutation induced neuronal over-excitation is normalized in the hippocampus but not the cortex which we are attributing to regional differences of microglia in both function and morphology. These Pten-mutant microglia may protect Pten mutant mice from developing spontaneous seizures, but cannot eliminate their heightened risk of provoked seizure. Collectively, our findings have revealed a potential protective role of microglia in an over-excited brain, underscoring the impact of microglial regional heterogeneity in disease development and highlighting their prospect as a therapeutic target for epilepsy.