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Amyloid pathology disrupts gliotransmitter release in astrocytes [1]

['Anup Gopalakrishna Pillai', 'Indian Institute Of Science Education', 'Research Pune', 'Pune', 'Suhita Nadkarni']

Date: 2022-08 

Accumulation of amyloid-beta (Aβ) is associated with synaptic dysfunction and destabilization of astrocytic calcium homeostasis. A growing body of evidence support astrocytes as active modulators of synaptic transmission via calcium-mediated gliotransmission. However, the details of mechanisms linking Aβ signaling, astrocytic calcium dynamics, and gliotransmission are not known. We developed a biophysical model that describes calcium signaling and the ensuing gliotransmitter release from a single astrocytic process when stimulated by glutamate release from hippocampal neurons. The model accurately captures the temporal dynamics of microdomain calcium signaling and glutamate release via both kiss-and-run and full-fusion exocytosis. We investigate the roles of two crucial calcium regulating machineries affected by Aβ: plasma-membrane calcium pumps (PMCA) and metabotropic glutamate receptors (mGluRs). When we implemented these Aβ-affected molecular changes in our astrocyte model, it led to an increase in the rate and synchrony of calcium events. Our model also reproduces several previous findings of Aβ associated aberrant calcium activity, such as increased intracellular calcium level and increased spontaneous calcium activity, and synchronous calcium events. The study establishes a causal link between previous observations of hyperactive astrocytes in Alzheimer’s disease (AD) and Aβ-induced modifications in mGluR and PMCA functions. Analogous to neurotransmitter release, gliotransmitter exocytosis closely tracks calcium changes in astrocyte processes, thereby guaranteeing tight control of synaptic signaling by astrocytes. However, the downstream effects of AD-related calcium changes in astrocytes on gliotransmitter release are not known. Our results show that enhanced rate of exocytosis resulting from modified calcium signaling in astrocytes leads to a rapid depletion of docked vesicles that disrupts the crucial temporal correspondence between a calcium event and vesicular release. We propose that the loss of temporal correspondence between calcium events and gliotransmission in astrocytes pathologically alters astrocytic modulation of synaptic transmission in the presence of Aβ accumulation.

Signaling by astrocytes is critical to information processing at synapses, and its aberration plays a central role in neurological diseases, especially Alzheimer’s disease (AD). A complete characterization of calcium signaling and the resulting pattern of gliotransmitter release from fine astrocytic processes are not accessible to current experimental tools. We developed a biophysical model that can quantitatively describe signaling by astrocytes in response to a wide range of synaptic activity. We show that AD-related molecular alterations disrupt the concurrence of calcium and gliotransmitter release events, a characterizing feature that enables astrocytes to influence synaptic signaling.

Introduction

Astrocytes, the most abundant glial cells, are now recognized for their role in maintaining normal brain functioning [1,2]. Apart from providing structural and energy support to neurons, these densely connected cells send ramified processes to neighboring synapses and form nonoverlapping synaptic islands [3,4]. A plethora of receptors are found on the astrocytic membrane; amongst them, metabotropic glutamate receptors (mGluRs) are specifically juxtaposed to the endoplasmic reticulum (ER) tubules and are expressed in high densities on compartments adjacent to synapses [5–7]. This remarkable configuration and the presence of inositol 1,4,5-trisphosphate receptor (IP 3 Rs) clusters on the ER allow fast and high amplitude calcium transients in the ramified processes of the astrocytes [8,9]. Along with these molecular components for Ca2+ signaling and their placement [10,11], astrocytes are also equipped with an elaborate apparatus for fast Ca2+-dependent release of gliotransmitters, which is comparable to neurons [12,13]. The link between calcium signaling and gliotransmission from astrocytic microdomains was established by a study that quantified Ca2+ transients using near-field imaging of astrocytic terminals loaded with a low-affinity calcium indicator in combination with a pH-sensitive vesicular glutamate transporter [5]. This technique allowed them to track subcellular Ca2+ events and the corresponding gliotransmitter release events simultaneously with good temporal resolution and brought to light several novel features of gliotransmission at subcellular compartments near synapses. First, the application of a short pulse of mGluR agonist evoked fast and stochastic Ca2+ events whose time course perfectly matched the ensuing gliotransmitter release events. The study also revealed tight spatial and temporal correlations between Ca2+ and exocytic fusion events. These results strongly indicate that gliotransmitter release events are coupled to microdomain Ca2+ events in individual astrocytic compartments. The study further reports the presence of two distinct classes of vesicle populations that differ in their fusion modes (kiss-and-run versus full-fusion) and in the timescales of endocytosis and reacidification. Several synaptotagmin (Syt) isoforms (calcium sensors for vesicle release) have been reported in astrocytes; amongst the subtypes, Syt4 and Syt7 are specifically associated with fast synchronous kiss-and-run and slow asynchronous full-fusion releases, respectively [14–17]. Several other studies also provide compelling evidence on the existence of dual release pathways and the ability of astrocytes to modulate synaptic strength in neuronal circuits [18–21].

The intimate spatial association between astrocytic compartments and synaptic junctions, together with the presence of a fast Ca2+ signaling machinery and multiple pathways for gliotransmitter release, provide the necessary framework for astrocytes to engage in bidirectional communication with neurons [22,23]. However, this pathway, an intrinsic component of communication by astrocytes, is heavily compromised under calcium overload, leading to excitotoxicity, loss of spines, and network connectivity [24,25]. Of relevance to the present study is the correlation between Aβ plaques seen in AD and the disruption of glutamate-mediated excitatory transmission [26]. Multiple lines of evidence point to a link between Aβ toxicity and calcium dysregulation in astrocytes [27]. Not only is Aβ a direct modulator of astrocytic Ca2+ [28], but it also elevates resting Ca2+ levels and synchronous Ca2+ events [29].

Even though several studies report on abnormal Ca2+ regulation in astrocytes exposed to Aβ, not much is known about the chronology of events and molecular mechanisms that disrupt the calcium signaling [30]. Nevertheless, both in vitro and post-mortem studies in AD brains highlight the role of two important Ca2+ regulating pathways, namely mGluRs [31,32] and PMCAs [33,34]. It has also been suggested that a significant part of the excess glutamate observed in AD brains has an astrocytic origin and is a consequence of Aβ signaling [35]. Again, the underlying biophysical links are not clear. These studies underscore that cellular degeneration in AD is orchestrated by a chain of signaling cascades extending all the way from Aβ to alterations in Ca2+ signaling and synaptic signaling by astrocytes [36]. Understanding the astrocytic mechanisms that are derailed under the influence Aβ is, therefore, crucial for advancing our knowledge of the pathogenesis of synaptic dysfunction that underlies the cognitive decline in AD [37].

Synergistic crosstalk between theory and experiments has led to some of the most profound insights in neuroscience and, more specifically into neurotransmitter release machinery and organization [38–40]. However, an equivalent biophysical modeling framework for calcium-dependent vesicle release and recycling does not exist, despite extensive knowledge on the calcium-binding kinetics of synaptotagmins [41], their different modes of vesicle release [18,42] and localization and lastly, calcium signaling [5] in the ramified processes that envelop synapses. Previous computational models have focused on global Ca2+ signals in astrocytes [43–45] and proposed phenomenological models to capture feedback to neurons via gliotransmission at a tripartite synapse [46–48]. Recently, studies have also shed light on the microscale mechanisms at fine astrocytic processes [49–52]. These models have made several valuable predictions on the contribution of astrocytes to brain function. The present study builds on this literature to fill the conspicuous gap (biophysical model of vesicle release and recycling) in the models and extend the existing computational modeling framework [53,54].

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[1] Url: https://journals.plos.org/ploscompbiol/article?id=10.1371/journal.pcbi.1010334

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