Astrocytes mediate long-lasting synaptic regulation of ventral tegmental area dopamine neurons.

The plasticity of glutamatergic transmission in the ventral tegmental area (VTA) represents a fundamental mechanism in the modulation of dopamine neuron burst firing and phasic dopamine release at target regions. These processes encode basic behavioral responses, including locomotor activity, learning and motivated behaviors. Here we describe a hitherto unidentified mechanism of long-term synaptic plasticity in mouse VTA. We found that the burst firing in individual dopamine neurons induces a long-lasting potentiation of excitatory synapses on adjacent dopamine neurons that crucially depends on Ca2+ elevations in astrocytes, mediated by endocannabinoid CB1 and dopamine D2 receptors co-localized at the same astrocytic process, and activation of pre-synaptic metabotropic glutamate receptors. Consistent with these findings, selective in vivo activation of astrocytes increases the burst firing of dopamine neurons in the VTA and induces locomotor hyperactivity. Astrocytes play, therefore, a key role in the modulation of VTA dopamine neuron functional activity.

Corrigendum: GABA tonic currents and glial cells are altered during epileptogenesis in a mouse model of Dravet syndrome.

[This corrects the article DOI: 10.3389/fncel.2022.919493.].

GABA tonic currents and glial cells are altered during epileptogenesis in a mouse model of Dravet syndrome.

Dravet Syndrome (DS) is a rare autosomic encephalopathy with epilepsy linked to Nav1.1 channel mutations and defective GABAergic signaling. Effective therapies for this syndrome are lacking, urging a better comprehension of the mechanisms involved. In a recognized mouse model of DS, we studied GABA tonic current, a form of inhibition largely neglected in DS, in brain slices from developing mice before spontaneous seizures are reported. In neurons from the temporal cortex (TeCx) and CA1 region, GABA tonic current was reduced in DS mice compared to controls, while in the entorhinal cortex (ECx) it was not affected. In this region however allopregnanonole potentiation of GABA tonic current was reduced in DS mice, suggesting altered extrasynaptic GABAA subunits. Using THIP as a selective agonist, we found reduced δ subunit mediated tonic currents in ECx of DS mice. Unexpectedly in the dentate gyrus (DG), a region with high δ subunit expression, THIP-evoked currents in DS mice were larger than in controls. An immunofluorescence study confirmed that δ subunit expression was reduced in ECx and increased in DG of DS mice. Finally, considering the importance of neuroinflammation in epilepsy and neurodevelopmental disorders, we evaluated classical markers of glia activation. Our results show that DS mice have increased Iba1 reactivity and GFAP expression in both ECx and DG, compared to controls. Altogether we report that before spontaneous seizures, DS mice develop significant alterations of GABA tonic currents and glial cell activation. Understanding all the mechanisms involved in these alterations during disease maturation and progression may unveil new therapeutic targets.

Somatostatin interneurons in the prefrontal cortex control affective state discrimination in mice.

The prefrontal cortex (PFC) is implicated in processing of the affective state of others through non-verbal communication. This social cognitive function is thought to rely on an intact cortical neuronal excitatory and inhibitory balance. Here combining in vivo electrophysiology with a behavioral task for affective state discrimination in mice, we show a differential activation of medial PFC (mPFC) neurons during social exploration that depends on the affective state of the conspecific. Optogenetic manipulations revealed a double dissociation between the role of interneurons in social cognition. Specifically, inhibition of mPFC somatostatin (SOM+), but not of parvalbumin (PV+) interneurons, abolishes affective state discrimination. Accordingly, synchronized activation of mPFC SOM+ interneurons selectively induces social discrimination. As visualized by in vivo single-cell microendoscopic Ca2+ imaging, an increased synchronous activity of mPFC SOM+ interneurons, guiding inhibition of pyramidal neurons, is associated with affective state discrimination. Our findings provide new insights into the neurobiological mechanisms of affective state discrimination.

Dynamic interactions between GABAergic and astrocytic networks.

Brain network activity derives from the concerted action of different cell populations. Together with interneurons, astrocytes play fundamental roles in shaping the inhibition in brain circuitries and modulating neuronal transmission. In this review, we summarize past and recent findings that reveal in neural networks the importance of the interaction between GABAergic signaling and astrocytes and discuss its physiological and pathological relevance.

Insights into the release mechanism of astrocytic glutamate evoking in neurons NMDA receptor-mediated slow depolarizing inward currents.

The gliotransmitter glutamate in different brain regions modulates neuronal excitability and synaptic transmission through a variety of mechanisms. Among the hallmarks of astrocytic glutamate release are the slow depolarizing inward currents (SICs) in neurons mediated by N-methyl-d-aspartate receptor activation. Different stimuli that evoke Ca2+ elevations in astrocytes induce neuronal SICs suggesting a Ca2+ -dependent exocytotic glutamate release mechanism of SIC generation. To gain new insights into this mechanism, we investigated the relationship between astrocytic Ca2+ elevations and neuronal SICs in mouse hippocampal slice preparations. Here we provide evidence that SICs, occurring either spontaneously or following a hypotonic challenge, are unchanged in the virtual absence of Ca2+ signal changes at astrocytic soma and processes, including spatially restricted Ca2+ microdomains. SICs are also unchanged in the presence of Bafilomycin A1 that after prolonged slice incubation depletes glutamate from astrocytic vesicles. We also found that hemichannels and TREK family channels-that recent studies proposed to mediate astrocytic glutamate release - are not involved in SIC generation. SICs are reduced by the volume-sensitive anion channel antagonists diisothiocyanatostilbene-2,2'-disulfonic acid (DIDS), quinine and fluoxetine, suggesting a possible contribution of these channels in SIC generation. Direct measurements of astrocytic glutamate release further confirm that hypotonicity-evoked gliotransmission is impaired following DIDS, quinine and fluoxetine while the exocytotic release of glutamate-that is proposed to mediate synaptic transmission modulation by astrocytes-remains unaffected. In conclusion, our data provide evidence that the release of glutamate generating SICs occurs independently on exocytotic Ca2+ -dependent glutamate release mechanism.

Interneuron-specific signaling evokes distinctive somatostatin-mediated responses in adult cortical astrocytes.

The signaling diversity of GABAergic interneurons to post-synaptic neurons is crucial to generate the functional heterogeneity that characterizes brain circuits. Whether this diversity applies to other brain cells, such as the glial cells astrocytes, remains unexplored. Using optogenetics and two-photon functional imaging in the adult mouse neocortex, we here reveal that parvalbumin- and somatostatin-expressing interneurons, two key interneuron classes in the brain, differentially signal to astrocytes inducing weak and robust GABAB receptor-mediated Ca2+ elevations, respectively. Furthermore, the astrocyte response depresses upon parvalbumin interneuron repetitive stimulations and potentiates upon somatostatin interneuron repetitive stimulations, revealing a distinguished astrocyte plasticity. Remarkably, the potentiated response crucially depends on the neuropeptide somatostatin, released by somatostatin interneurons, which activates somatostatin receptors at astrocytic processes. Our study unveils, in the living brain, a hitherto unidentified signaling specificity between interneuron subtypes and astrocytes opening a new perspective into the role of astrocytes as non-neuronal components of inhibitory circuits.