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

Abstract

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.

Increased Synaptic ATP Release and CD73-Mediated Formation of Extracellular Adenosine in the Control of Behavioral and Electrophysiological Modifications Caused by Chronic Stress

“…These results show that the evoked release of ATP in synapses is increased upon repeated stress, associated with mood and memory dysfunction (Figure ), in clear opposition to the previously reported decreased release of ATP from astrocytes upon emergence of depressive-like behavior. ,,, These apparently contradictory findings should be interpreted in view of the different roles of ATP within synapses and between synapses: within synapses released ATP from nerve terminals sustains the ecto-nucleotidase-mediated formation of extracellular adenosine to selectively activate adenosine A 2A R and bolster synaptic plasticity processes. − In contrast, ATP released from astrocytes is mostly engaged in heterosynaptic depression mainly through the activation of A 1 R − as well in the coordination of microglia recruitment through P 2Y12 R and microglia activation through P 2X7 R . Thus, astrocytically released ATP and synaptically released ATP fulfill parallel, different, and complementary roles in the global control of neuronal circuits and neuroinflammation and in the local control of synaptic plasticity, respectively.…”

“…Adenosine mainly acts through inhibitory adenosine A 1 receptors and facilitatory adenosine A 2A receptors (A 2A R) to assist encoding salience of information in neuronal circuits . This parallel activation of A 1 R and A 2A R is ensured by different sources of adenosine: activation of A 1 R results from ATP/adenosine released from astrocytes, − from microglia , or from postsynaptic compartments of neurons through bidirectional nucleoside transporters, whereas synaptically released ATP-derived formation of extracellular adenosine through ecto-nucleotidases is selectively associated with the activation of adenosine A 2A R controlling synaptic plasticity processes. − Understanding the dynamics of the adenosine modulation system is relevant to control neurodegeneration in accordance with the view that chronic brain diseases begin by a dysfunction and damage of synapses (reviewed in refs and ), mainly of excitatory synapses. , …”

Astrocytes gate long-term potentiation in hippocampal interneurons

“…Stereotactic virus injection was conducted as described previously (Shen et al 2021;Shen et al 2022). Briefly, adult mice were deeply anesthetized with sodium pentobarbital (50 mg/kg) and secured in a stereotaxic device with ear bars (RWD, 68930), while their body temperature was maintained at approximately 37 °C using a heating blanket.…”

“…Whole-cell recordings were performed on stratum radiatum astrocytes using pipettes with a resistance of 8-10 MΩ and filled with an intracellular solution containing (in mM) 130 K-Gluconate, 20 HEPES, 3 ATP-Na 2 , 10 D-Glucose, 1 MgCl 2 , 0.2 EGTA (280)(281)(282)(283)(284)(285)(286)(287)(288)(289)(290). In a subset of experiments, 0.14 mM CaCl 2 and 0.45 mM EGTA were included in the upper intracellular solution to maintain a stable level of astrocytic concentration (calculation by Web-MaxChelator) (Shen et al 2022;Henneberger et al 2010). Astrocytes were identified as described previously (Shen et al 2021;Shen et al 2022).…”

“…In a subset of experiments, 0.14 mM CaCl 2 and 0.45 mM EGTA were included in the upper intracellular solution to maintain a stable level of astrocytic concentration (calculation by Web-MaxChelator) (Shen et al 2022;Henneberger et al 2010). Astrocytes were identified as described previously (Shen et al 2021;Shen et al 2022).…”