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 (GABABRs). It is well documented that astrocytes express GABABRs and respond to GABAergic network activity. However, little is known about whether astrocytic GABABRs 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 GABABRs and GAT‐3. SOM‐INs depress excitatory neurotransmission by activating presynaptic GABABRs and astrocytic GABABRs, the latter inducing the release of ATP/adenosine. In turn, adenosine inhibits excitatory synaptic transmission by activating presynaptic adenosine A1 receptors (A1Rs). Overall, our results reveal a novel mechanism that SOM‐INs activation‐induced synaptic depression is partially mediated by the activation of astrocytic GABABRs.

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.

Long-term potentiation is involved in physiological process like learning and memory, motor learning and sensory processing, and pathological conditions such as addiction. In contrast to the extensive studies on the mechanism of long-term potentiation on excitatory glutamatergic synapse onto excitatory neurons (LTPE→E), the mechanism of LTP on excitatory glutamatergic synapse onto inhibitory neurons (LTPE→I) remains largely unknown. In the central nervous system, astrocytes play an important role in regulating synaptic activity and participate in the process of LTPE→E, but their functions in LTPE→Iremain incompletely defined. Using electrophysiological, pharmacological, confocal calcium imaging, chemogenetics and behavior tests, we studied the role of astrocytes in regulating LTPE→Iin the hippocampal CA1 region and their impact on cognitive function. We show that LTPE→Iin stratum oriens of hippocampal CA1 is astrocyte independent. However, in the stratum radiatum, synaptically released endocannabinoids increases astrocyte Ca2+via type-1 cannabinoid receptors, stimulates D-serine release, and potentiate excitatory synaptic transmission on inhibitory neuron through the activation of (N-methyl-D-aspartate) NMDA receptors. We also revealed that chemogentic activation of astrocytes is sufficient to induce NMDA-dependentde novoLTPE→Iin the stratum radiatum of hippocampus. Furthermore, we found that disrupt LTPE→Iby knockdwon γCaMKII in interneurons of stratum radiatum resulted in dramatic memory impairment. Our findings suggest that astrocytes release D-serine, which activates NMDA receptors to regulate LTPE→I, and that cognitive function is intricately linked with the proper functioning of this LTPE→Ipathway.