Preferential pruning of inhibitory synapses by microglia contributes to alteration of the balance between excitatory and inhibitory synapses in the hippocampus in temporal lobe epilepsy

Abstract

BackgroundA consensus has formed that neural circuits in the brain underlie the pathogenesis of temporal lobe epilepsy (TLE). In particular, the synaptic excitation/inhibition balance (E/I balance) has been implicated in shifting towards elevated excitation during the development of TLE.MethodsSprague Dawley (SD) rats were intraperitoneally subjected to kainic acid (KA) to generate a model of TLE. Next, electroencephalography (EEG) recording was applied to verify the stability and detectability of spontaneous recurrent seizures (SRS) in rats. Moreover, hippocampal slices from rats and patients with mesial temporal lobe epilepsy (mTLE) were assessed using immunofluorescence to determine the alterations of excitatory and inhibitory synapses and microglial phagocytosis.ResultsWe found that KA induced stable SRSs 14 days after status epilepticus (SE) onset. Furthermore, we discovered a continuous increase in excitatory synapses during epileptogenesis, where the total area of vesicular glutamate transporter 1 (vGluT1) rose considerably in the stratum radiatum (SR) of cornu ammonis 1 (CA1), the stratum lucidum (SL) of CA3, and the polymorphic layer (PML) of the dentate gyrus (DG). In contrast, inhibitory synapses decreased significantly, with the total area of glutamate decarboxylase 65 (GAD65) in the SL and PML diminishing enormously. Moreover, microglia conducted active synaptic phagocytosis after the formation of SRSs, especially in the SL and PML. Finally, microglia preferentially pruned inhibitory synapses during recurrent seizures in both rat and human hippocampal slices, which contributed to the synaptic alteration in hippocampal subregions.ConclusionsOur findings elaborately characterize the alteration of neural circuits and demonstrate the selectivity of synaptic phagocytosis mediated by microglia in TLE, which could strengthen the comprehension of the pathogenesis of TLE and inspire potential therapeutic targets for epilepsy treatment.

Single-Cell Transcriptomic Analyses of Brain Parenchyma in Patients With New-Onset Refractory Status Epilepticus (NORSE)

“… 29 Their ability to modulate synapses and clear damaged neurons has been implicated in altering the balance between excitatory and inhibitory synapses, potentially favoring excitation, as observed in temporal lobe epilepsy. 30 By contrast, macrophage depletion was associated with a significant reduction in seizure frequency in mice after acute viral encephalitis. 31 This may explain the positive correlation between the proportion of microglial cells or infiltrating macrophages and the ratio between the excitatory and GABAergic neurons.…”

Abscisic Acid rescues behavior in adult female mice in Attention Deficit Disorder with Hyperactivity model of dopamine depletion by regulating microglia and increasing Vesicular GABA Transporter expression

“…Beyond the inflammatory properties, microglia activity is key in the regulation of the excitation/inhibition (E/I) ratio (Fan et al 2023), and the E/I imbalance has been found as a fundamental factor underlying a variety of neuropsychiatric and neurodevelopmental disorders (LeBlanc and Fagiolini 2011). In fact, E/I imbalance in ACC and insula (Bai et al 2019b) is associated to higher nociception animal models of neurodevelopmental disorders (Qi et al 2022).…”

Abscisic Acid rescues behavior in adult female mice in Attention Deficit Disorder with Hyperactivity model of dopamine depletion by regulating microglia and vesicular GABA transporter

“…Beyond the inflammatory properties, microglia activity is key in the regulation of the excitation/inhibition (E/I) ratio (106), and the E/I imbalance has been found as a fundamental factor underlying a variety of neuropsychiatric and neurodevelopmental disorders (107). In fact, E/I imbalance in ACC and insula (108) is associated to higher nociception animal models of neurodevelopmental disorders (109).…”