Astrocyte regulation of synaptic signaling in psychiatric disorders

Abstract

Over the last 15 years, the field of neuroscience has evolved toward recognizing the critical role of astroglia in shaping neuronal synaptic activity and along with the pre-and postsynapse is now considered an equal partner in tripartite synaptic transmission and plasticity. The relative youth of this recognition and a corresponding deficit in reagents and technologies for quantifying and manipulating astroglia relative to neurons continues to hamper advances in understanding tripartite synaptic physiology. Nonetheless, substantial advances have been made and are reviewed herein. We review the role of astroglia in synaptic function and regulation of behavior with an eye on how tripartite synapses figure into brain pathologies underlying behavioral impairments in psychiatric disorders, both from the perspective of measures in postmortem human brains and more subtle influences on tripartite synaptic regulation of behavior in animal models of psychiatric symptoms. Our goal is to provide the reader a wellreferenced state-of-the-art understanding of current knowledge and predict what we may discover with deeper investigation of tripartite synapses using reagents and technologies not yet available.

Distribution patterns of astrocyte populations in the human cortex

“…Astrocytes are highly metabolically active cells and alterations in their homeostasis and dysfunction are a key feature of many neurodegenerative, neurodevelopmental, psychiatric, in ammatory, prion and other diseases [5,12,[30][31][32][33][34][35], and more recently, brain ageing [36]. Recent single-cell transcriptomics studies have identi ed further complexity in astrocyte function and their response to injury and disease [37,38], and there is evidence to suggest that astrocytes contribute to the spread of abnormal protein aggregates throughout the brain [6, 9,12].…”

NPAS4 supports drug-cue associations and relapse-like behavior through regulation of the cell type-specific activation balance in the nucleus accumbens

“…Finally, the largest number of cocaine-induced DEGs are found in the non-neuronal cells, including astrocytes and oligodendrocytes, and most of those DEGs are not influenced by NPAS4, which is strictly neuronal. Astrocytes play an important role in shaping synaptic transmission associated with drug-cue reactivity 91 , and the cocaine conditioning-induced changes in glial gene expression highlight the strong engagement of these non-neuronal populations in drug-related behavior.…”

Looking to the stars for answers: Strategies for determining how astrocytes influence neuronal activity

“…In addition to neurotransmitter uptake systems, astrocytes express a myriad of ionotropic and metabotropic neurotransmitter receptors which allow them to sense and respond to synaptic activity [19] , [20] . Moreover, the majority of astrocytes contact blood vessels, serving as an intermediary between neurons and the neurovascular network [21] , both to provide metabolic support and to deliver the required precursors for the generation of GABA and glutamate, a cellular function that is required for normal synaptic communication and physiological processes [22] . Because of the large body of work detailing their role in modulating synaptic plasticity, astrocytes are now appreciated as active components of neural networks with diverse and functional roles in neuronal processing.…”

“…Indeed, many of the cellular functions of astroglia, including aspects of the homeostatic support of neurons and their ability to influence synaptic communication, rely on intracellular Ca 2+ signaling [26] . Consequently, a considerable body of work now demonstrates that tightly regulated astroglia Ca 2+ dynamics and the related homeostatic function of astroglia are required for many normal physiological processes [27] , [28] , with disruption of these cellular systems linked to the pathophysiology of neuropsychiatric diseases, including substance use disorders [22] , [29] , [30] , [31] , [32] , [33] , [34] , [35] , [36] , [37] , [38] , [39] , [40] , [41] , [42] , [43] , [44] , [45] . As we progress further in understanding the role of astroglia in shaping neural communication, there is an increasing need to evaluate astrocytic spatiotemporal Ca 2+ dynamics to better understand the mechanistic underpinnings of how astrocytes influence local neurotransmission at both the single cell and circuit-level in vivo .…”

“…Evidence does indeed exist supporting astroglial expression of low levels of glutamate-containing vesicles and alternative isoforms of SNARE proteins that support vesicular release [114] , implying that astrocytes are capable of Ca 2+ -dependent mechanisms of gliotransmitter release. Furthermore, as discussed above, astrocytic regulation of synaptic activity also extends beyond vesicular or non-vesicular gliotransmission, as astrocytes are responsible for (1) the delivery of the precursors needed to generate key neurotransmitters, (2) the reuptake of neuroactive chemicals from the synaptic cleft and cessation of synaptic activity, (3) the shaping the physical space that neurotransmission occurs in, (4) the ion buffering required to support action potential generation, and (5) the metabolic support of local neurons [1] , [22] , with the several of these processes occurring via Ca 2+ -dependent mechanisms. As outlined throughout this review, our perspective is that Ca 2+ dynamics are essential for astroglia to respond to and influence the synaptic environment and regulate the local neuronal activity and circuit-level communication underlying complex behavioral responses.…”