Recent studies have revealed synaptic dysfunction to be a hallmark of various psychiatric diseases, and that glial cells participate in synapse formation, development, and plasticity. Glial cells contribute to neuroinflammation and synaptic homeostasis, the latter being essential for maintaining the physiological function of the central nervous system (CNS). In particular, glial cells undergo gliotransmission and regulate neuronal activity in tripartite synapses via ion channels (gap junction hemichannel, volume regulated anion channel, and bestrophin-1), receptors (for neurotransmitters and cytokines), or transporters (GLT-1, GLAST, and GATs) that are expressed on glial cell membranes. In this review, we propose that dysfunction in neuron-glia interactions may contribute to the pathogenesis of neurodevelopmental disorders. Understanding the mechanisms of neuron-glia interaction for synapse formation and maturation will contribute to the development of novel therapeutic targets of neurodevelopmental disorders.

Tonic inhibition in the brain is mediated through an activation of extrasynaptic GABA_A receptors by the tonically released GABA, resulting in a persistent GABAergic inhibitory action. It is one of the key regulators for neuronal excitability, exerting a powerful action on excitation/inhibition balance. We have previously reported that astrocytic GABA, synthesized by monoamine oxidase B (MAOB), mediates tonic inhibition via GABA-permeable bestrophin 1 (Best1) channel in the cerebellum. However, the role of astrocytic GABA in regulating neuronal excitability, synaptic transmission, and cerebellar brain function has remained elusive. Here, we report that a reduction of tonic GABA release by genetic removal or pharmacological inhibition of Best1 or MAOB caused an enhanced neuronal excitability in cerebellar granule cells (GCs), synaptic transmission at the parallel fiber-Purkinje cell (PF-PC) synapses, and motor performance on the rotarod test, whereas an augmentation of tonic GABA release by astrocyte-specific overexpression of MAOB resulted in a reduced neuronal excitability, synaptic transmission, and motor performance. The bidirectional modulation of astrocytic GABA by genetic alteration of Best1 or MAOB was confirmed by immunostaining and in vivo microdialysis. These findings indicate that astrocytes are the key player in motor coordination through tonic GABA release by modulating neuronal excitability and could be a good therapeutic target for various movement and psychiatric disorders, which show a disturbed excitation/inhibition balance. Significance Tonic inhibition plays critical roles in cognitive functions under physiological and pathological conditions by controlling neuronal excitability. Although we have previously reported that cerebellar tonic inhibition is critically dependent on both the synthesis of GABA through monoamine oxidase B (MAOB) enzyme and the release via the bestrophin 1 (Best1) channel, the role of astrocytic GABA in cerebellar function in vivo has remained elusive. Here, we report that a reduction of tonic GABA release by genetic or pharmacological removal of Best1 or MAOB caused enhanced neuronal excitability, synaptic transmission, and motor performance on the rotarod test, whereas an augmentation of tonic GABA release by astrocyte-specific overexpression of MAOB caused opposite results. Our findings suggest the actions of astrocytic GABA in excitation/inhibition balance and motor coordination.

Yoo Sung Kim and Bo-Eun Yoon. Exp Neurobiol 2017;26:122-31. https://doi.org/10.5607/en.2017.26.3.122

Background: Glutamate is the major neurotransmitter that mediates a principal form of excitatory synaptic transmission in the brain. From the presynaptic terminals of neurons, glutamate is released upon exocytosis of the glutamate-packaged vesicles. In recent years, astrocytes are also known to release glutamate via various routes to modulate synaptic transmission. In particular, we have characterized a glutamate-permeable Ca²⁺-activated anion channel encoded by Bestrophin 1 gene (Best1) that is responsible for Ca²⁺-dependent, channel-mediated glutamate release in astrocyte. Best1 channel contains a large pore that is readily permeable to large molecules such as glutamate and GABA. In those studies we obtained permeability ratio of glutamate to Cl^- in heterologously expressed mouse Best1 in HEK293T cells and in endogenously expressed mouse Best1 in cultured astrocytes. However, up to now, glutamate permeability of the native Best1 channel in vivo has not been reported. Findings: In whole-cell recordings of CA1 hippocampal astrocytes, we found that opening of Best1 channel upon activation of a Gq-coupled GPCR, protease-activated receptor 1 (PAR1) generated the anion current carried by glutamate via Ca²⁺ increase. This Ca²⁺-evoked glutamate-mediated anion current was unaffected by pretreatment of the inhibitors for a gap junction hemi-channel or Ca²⁺-activated K⁺ conductance. This astrocytic anion conductance carried by glutamate was mediated by Best1 channel expression in CA1 hippocampal astrocytes, because Best1 knock-down by shRNA expression eliminated astrocytic glutamate conductance by PAR-1 activation. However, we found that these astrocytes showed a deviation in reversal potential of Best1-mediated current from the predicted value. By performing dual patch recording, we concluded that the deviation of reversal potential is due to incomplete space clamping arising from extremely leaky membrane (input resistance ranging 1–3 MΩ), very low length constant of astrocytic processes, and the localization of Best1 channel in distal microdomains near synapses. Based on the relative shift of reversal potentials by ion substitutions, we estimated the permeability ratio of glutamate and Cl^- (P_glutamate/P_Cl) as 0.53. Conclusions: Our study shows that Best1, located at the microdomains near the synaptic junctions, has a significantly high permeability to glutamate in vivo, serving as the prominent glutamate-releasing channel in astrocytes, mediating the release of various gliotransmitters in the brain, and playing an important role in modulating synaptic transmission.

The amyloid-β (Aβ) hypothesis has been the leading explanation for the pathogenesis of Alzheimer’s disease (AD). The most common traits of AD are cognitive impairments and memory loss, which are associated with the accumulation of Aβ. Aβ aggregates activate glial cells, which in turn remove Aβ. Because microglia act as immune cells in the brain, most glia-related studies of AD have focused primarily on this cell type. However, astrocytes, another type of glial cell, also participate in the brain immune system, synaptic formation, brain homeostasis, and various other brain functions. Accordingly, many studies on the underlying mechanisms of AD have investigated not only neurons but also glial cells. Although these studies suggest that microglia and astrocytes are effective targets for AD therapeutics, other recent studies have raised questions regarding whether microglial cells and/or astrocytes serve a neuroprotective or neurotoxic function in AD. To gain a better understanding of the mechanisms of AD and identify novel targets for AD treatment, in this review, we consider the role of both microglia and astrocytes in AD.

Kim YS, et al. Exp Neurobiol. 2017 Aug;26(4):206-212. https://doi.org/10.5607/en.2017.26.4.206