Microglia-neuron communication in ischemic stroke: from homeostatic signaling to pathological remodeling and therapeutic targeting

Ischemic stroke profoundly disrupts the homeostatic dialogue between microglia and neurons, converting a physiological surveillance network into a dynamic, injury-responsive, and spatially heterogeneous communication system. Under physiological conditions, neurons regulate microglia through diverse signaling pathways, while microglia support neuronal health via synaptic remodeling, inflammatory regulation, metabolic balance, and debris clearance. Following cerebral ischemia, cascades involving excitotoxicity, energy failure, ionic imbalance, damage-associated molecular patterns (DAMPs), complement activation, and cell death signals rapidly reprogram this bidirectional communication. In this Review, we propose the Microglia-Neuron Communication Continuum (MNCC) model as a conceptual framework for understanding post-stroke microglia-neuron crosstalk. The MNCC model conceptualizes these interactions as a multidimensional continuum defined by three core axes: time, communication mode, and functional outcome. Along the temporal axis, crosstalk evolves from the hyperacute and acute phases to the subacute and chronic stages. Along the communication-mode axis, interactions span direct contact-dependent mechanisms and indirect soluble signaling pathways. Along the functional-output axis, the biological consequences range from damage amplification to tissue repair and chronic maladaptation. Using this framework, we first summarize the physiological basis of bidirectional microglia-neuron signaling under homeostatic conditions. We then examine how ischemic stroke reprograms this network across distinct temporal stages and spatial niches, emphasizing that post-stroke crosstalk is a continuous, context-dependent, spatially heterogeneous, and functionally plastic process. Finally, we discuss current and emerging therapeutic strategies through the lens of the MNCC model, focusing on temporal matching, dominant communication modes, regional heterogeneity, and translational barriers. A deeper understanding of this communication continuum may facilitate the development of targeted interventions that restrain harmful signaling, preserve beneficial interactions, and ultimately improve long-term neurological recovery after ischemic stroke.