Abnormal innate and learned behavior induced by neuron-microglia miscommunication is related to CA3 reconfiguration

Neuron-microglia communication through the Cx3cr1-Cx3cl1 axis is essential for the development and refinement of neural circuits, which determine their function into adulthood. In the present work we set out to extend the behavioral characterization of Cx3cr1^-/- mice evaluating innate behaviors and spatial navigation, both dependent on hippocampal function. Our results show that Cx3cr1-deficient mice, which show some changes in microglial and synaptic terminals morphology and density, exhibit alterations in activities of daily living and in the rapid encoding of novel spatial information that, nonetheless, improves with training. A neural substrate for these cognitive deficiencies was found in the form of synaptic dysfunction in the CA3 region of the hippocampus, with a marked impact on the mossy fiber (MF) pathway. A network analysis of the CA3 microcircuit reveals the effect of these synaptic alterations on the functional connectivity among CA3 neurons with diminished strength and topological reorganization in Cx3cr1-deficient mice. Neonatal population activity of the CA3 region in Cx3cr1-deficient mice shows a marked reorganization around the giant depolarizing potentials, the first form of network-driven activity of the hippocampus, suggesting that alterations found in adult subjects arise early on in postnatal development, a critical period of microglia-dependent neural circuit refinement. Our results show that interruption of the Cx3cr1-Cx3cl1/neuron-microglia axis leads to changes in CA3 configuration that affect innate and learned behaviors.