The Interactions of Tau, RNA, and Stress Granules in Neurodegenerative Disease: A Comprehensive Review.

During the development of the nervous system, neurons form synaptic connections that far exceed functional requirements (). To establish efficient and functional neural circuits and ensure the proper execution of brain physiological functions, unstable or weak synapses must be selectively eliminated by glial cells, a process known as synaptic pruning (). As a member of glial cells, microglia play a pivotal role in synaptic pruning. Under physiological conditions, microglia respond to neuronal activity and external stimuli by continuously extending and retracting their processes to monitor synapses (). In chronic neuroinflammatory environments of various neurological disease models—such as epilepsy, Alzheimer’s disease (AD), multiple sclerosis, and depression—the microglia-mediated synaptic pruning pathways can become hyperactivated in specific brain regions, engulfing normal synapses and neurons. This abnormal phagocytic activity leads to cognitive decline and seizure threshold reduction (–). In patients and animal models of epilepsy, hippocampal microglia exhibit a persistently activated state (). Activated microglia drive epileptogenesis and exacerbate cognitive deficits via abnormal synaptic pruning at both structural and functional levels. Structurally, three-dimensional serial-section electron microscopy shows that during the formation of spontaneous recurrent seizures (SRS), microglia in the hippocampal cornu ammonis 1 (CA1) stratum radiatum, cornu ammonis 3 (CA3) mossy fiber layer, and dentate gyrus polymorphic layer preferentially engulf glutamate decarboxylase 65 (GAD65)-positive inhibitory presynaptic terminals, while the area of vesicular glutamate transporter 1 (vGluT1)-positive excitatory synapses simultaneously expands. This results in a structural excitatory/inhibitory (E/I) imbalance characterized by a relative increase in excitatory synapses and an absolute reduction in inhibitory synapses (). Functionally, in direct co-culture models of excitatory neurons and microglia, activated microglia significantly enhance synaptic engulfment, leading to reduced dendritic spine density and a decreased total number of synapses (). As dendritic spines serve as the structural basis of synaptic plasticity, their loss directly impairs the induction and maintenance of long-term potentiation (LTP), thereby disrupting learning and memory processes. Analyses of epileptic tissue further indicate that the degree of microglial activation positively correlates with seizure duration, frequency, and postoperative cognitive dysfunction (). However, the mechanisms by which microglia pathologically prune synapses within epileptic foci remain incompletely defined. Available evidence suggests that epileptic discharges can reprogram the molecular recognition landscape that governs neuron–glia interactions, thereby disturbing the expression level and spatiotemporal distribution of three major classes of signals—find-me, eat-me, and don’t-eat-me cues—and ultimately initiating aberrant synaptic pruning. The following sections therefore examine how these signaling systems are altered in epilepsy, what functions they appear to serve in this context, and which mechanisms are most likely to drive pathological synapse loss. Particular emphasis is placed on their therapeutic implications.