Activity-Dependent Plasticity of Astroglial Potassium and Glutamate Clearance

Abstract

Recent evidence has shown that astrocytes play essential roles in synaptic transmission and plasticity. Nevertheless, how neuronal activity alters astroglial functional properties and whether such properties also display specific forms of plasticity still remain elusive. Here, we review research findings supporting this aspect of astrocytes, focusing on their roles in the clearance of extracellular potassium and glutamate, two neuroactive substances promptly released during excitatory synaptic transmission. Their subsequent removal, which is primarily carried out by glial potassium channels and glutamate transporters, is essential for proper functioning of the brain. Similar to neurons, different forms of short- and long-term plasticity in astroglial uptake have been reported. In addition, we also present novel findings showing robust potentiation of astrocytic inward currents in response to repetitive stimulations at mild frequencies, as low as 0.75 Hz, in acute hippocampal slices. Interestingly, neurotransmission was hardly affected at this frequency range, suggesting that astrocytes may be more sensitive to low frequency stimulation and may exhibit stronger plasticity than neurons to prevent hyperexcitability. Taken together, these important findings strongly indicate that astrocytes display both short- and long-term plasticity in their clearance of excess neuroactive substances from the extracellular space, thereby regulating neuronal activity and brain homeostasis.

Sex differences in astrocyte and microglia responses immediately following middle cerebral artery occlusion in adult mice

“…Functionally, astrocytes have a vital role in maintaining, mediating and restoring neuronal function during physiologic and pathologic conditions (Araque et al, 1999; del Zoppo, 2010; Nedergaard et al, 2010). In this role, astrocytes are key in maintaining K + homeostasis (Kofuji and Newman, 2004), removal of excess glutamate (Cheung et al, 2015), local blood flow regulation (Attwell et al, 2010; Kim et al, 2015), synaptogenesis and synaptic maintenance (Franke et al, 2012), among other functions. On the other hand, astrocyte dysfunction after ischemia may exacerbate brain injury via aberrant astrocyte Ca 2+ signaling which can result in glutamate excitotoxicity (Nedergaard et al, 2010) or through the release of astrocyte-derived proteins and small molecular messengers such as ATP, TNFα, and S100β, which further increases neuroinflammation (Agulhon et al, 2012; Liu et al, 2011; Pascual et al, 2012).…”

CREB decreases astrocytic excitability by modifying subcellular calcium fluxes via the sigma-1 receptor

“…To our knowledge, this is the first report demonstrating that astrocytes, like neurons, do have long-term and transient intrinsic plasticity-like phenomena or 'cellular' memory in terms of calcium responses. Although the idea of structural and functional plasticity of astrocytes has already been explored in other laboratories [49], previous reports dealt with short-term changes in gliotransmission (less than 30 minutes long), and these changes were, moreover, not mediated by a transcription factor and hence gene expression [50][51]. Because CREB reduces rather than increases astrocyte excitability, it appears that we might have discovered an LTD-like phenomena that may help memory consolidation by inducing a negative feedback loop that maintains neural networks in stable states or very long transients [52].…”

Plasminogen binding inhibitors demonstrate unwanted activities on GABA A and glycine receptors in human iPSC derived neurons

“…Astrocyte functionality is heterogenous and even though the contribution to brain function is not fully understood numerous key features associates to astrocyte biology. There are several excellent reviews highlighting the diversity of astrocytic function including glutamineglutamate/GABA cycle (199,200), gliotransmission (201), calcium signaling (202,203), potassium homeostasis (204), energy storage and support (205,206), astrogliosis (207)(208)(209)(210), water homeostasis (211), astrocyte-neuron lactate shuttle (212), thyroid metabolism (196), synaptogenesis (213), regulation of synaptic behavior and neurotransmission (214)(215)(216) and BBB interactions (217). Evaluation of glutamate uptake, inflammatory responsiveness, and calcium signaling are commonly performed in hPSC derived astrocytic models and is used as a measurement of astrocytic identity.…”