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.

BACKGROUND: A 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. METHODS: Sprague 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. RESULTS: We 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. CONCLUSIONS: Our 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.

Somatostatin interneurons inhibit excitatory transmission mediated by astrocytic GABAB and presynaptic GABAB and adenosine A1 receptors in the hippocampus.

GABAergic network activity has been established to be involved in numerous physiological processes and pathological conditions. Extensive studies have corroborated that GABAergic network activity regulates excitatory synaptic networks by activating presynaptic GABAB receptors (GABAB Rs). It is well documented that astrocytes express GABAB Rs and respond to GABAergic network activity. However, little is known about whether astrocytic GABAB Rs regulate excitatory synaptic transmission mediated by GABAergic network activity. To address this issue, we combined whole-cell recordings, optogenetics, calcium imaging, and pharmacological approaches to specifically activate hippocampal somatostatin-expressing interneurons (SOM-INs), a type of interneuron that targets pyramidal cell dendrites, while monitoring excitatory synaptic transmission in CA1 pyramidal cells. We found that optogenetic stimulation of SOM-INs increases astrocyte Ca2+ signaling via the activation of astrocytic GABAB Rs and GAT-3. SOM-INs depress excitatory neurotransmission by activating presynaptic GABAB Rs and astrocytic GABAB Rs, the latter inducing the release of ATP/adenosine. In turn, adenosine inhibits excitatory synaptic transmission by activating presynaptic adenosine A1 receptors (A1 Rs). Overall, our results reveal a novel mechanism that SOM-INs activation-induced synaptic depression is partially mediated by the activation of astrocytic GABAB Rs.