Does rapid and physiological astrocyte–neuron signalling amplify epileptic activity?

Abstract

The hippocampus is a key brain region in the pathophysiology of mesial temporal lobe epilepsy. Long-term changes of its architecture and function on the network and cellular level are well documented in epilepsy. Astrocytes can control many aspects of neuronal function and their long-term alterations over weeks, months and years play an important role in epilepsy. However, a pathophysiological transformation of astrocytes does not seem to be required for astrocytes to contribute to epileptic activity. Some of the properties of physiological astrocyte-neuron communication could allow these cells to exacerbate or synchronize neuronal firing on shorter time scales of milliseconds to minutes. Therefore, these astrocyte-neuron interactions are increasingly recognized as potential contributors to epileptic activity. Fast and reciprocal communication between astrocytes and neurons is enabled by a diverse set of mechanisms that could both amplify and counteract epileptic activity. They may thus promote or cause development of epileptic activity or inhibit it. Mechanisms of astrocyte-neuron interactions that can quickly increase network excitability involve, for example, astrocyte Ca and Na signalling, K buffering, gap junction coupling and metabolism. However, rapid changes of astrocyte neurotransmitter uptake and morphology may also underlie or support development of network hyperexcitability. The temporal characteristics of these interactions, their ability to synchronize neuronal activity and their net effect on network activity will determine their contribution to the emergence or maintenance of epileptic activity.

Altered gene expression profile in a mouse model of SCN8A encephalopathy

“…In our model of monogenic SCN8A epilepsy, reactive astrocytosis occurs in response to seizures and may be neuroprotective via secretion of chemokines, cytokines, growth factors, and extracellular matrix components that promote neuronal survival (Banker, 1980; Bush et al, 1999; Myer et al, 2006; Zhang et al, 2016). Recent studies indicate that reactive astrocytosis comprises a continuum of context-dependent changes that are regulated by specific signaling events (Crunelli et al, 2015; Henneberger, 2016; Sofroniew and Vinters, 2010; Zamanian et al, 2012; Zhang et al, 2016), consistent with either a protective or pathogenic role in Scn8a encephalopathy.…”

Astrocyte lineage cells are essential for functional neuronal differentiation and synapse maturation in human iPSC‐derived neural networks

“…In contrast to their well‐studied roles in the developmental maturation and in the regulation of synaptic transmission, relatively few studies have described direct effects of astrocytes on maturation and regulation of neuronal excitability. Astrocytes play important roles during epileptic seizures, but appear to affect neuronal excitability rather indirectly during epileptic network activity (Henneberger, ; Robel & Sontheimer, ; Zuchero & Barres, ). Regarding direct effects of astrocyte‐like cells on neuronal excitability, an upregulation of Na + current density in hippocampal neurons by astrocyte‐released proteins has been suggested (Igelhorst, Niederkinkhaus, Karus, Lange, & Dietzel, ; Niederkinkhaus, Marx, Hoffmann, & Dietzel, ).…”

Adenosine A2A receptor and ecto-5′-nucleotidase/CD73 are upregulated in hippocampal astrocytes of human patients with mesial temporal lobe epilepsy (MTLE)

“…Astrocytes influence the pathogenesis and pathophysiology of epilepsy by creating an excitatory feedback loop via the release of gliotransmitters, such as glutamate, D-serine, and ATP, and/ or by acting upstream on the homeostatic control of uptake, degradation, and recycling of neurotransmitters and neuromodulators, including adenosine (reviewed in [48]). In addition to their local modulatory role to exacerbate or synchronize neuronal firing on shorter timescales of milliseconds to minutes, long-lasting volume and morphological changes (e.g., perisynaptic branches swelling, extension, or retraction of processes) of reactive astrocytes may transform these cells into aberrant synaptic network integrators due to inhibition of neurotransmitter clearance, defective potassium buffering capacity, altered Ca 2+ signal propagation, and uncoupling of gap junction-mediated cell communication (reviewed in [54]). The astrocytic localization of the A 2A receptor strengthens a role for these cells in epilepsy, which may be associated with the proposed modulation of glutamate transport and release [11][12][13].…”