Role of astrocyte-synapse interactions in CNS disorders

Abstract

Astrocytes comprise half of the cells in the brain. Although astrocytes have traditionally been described as playing a supportive role for neurons, they have recently been recognized as active participants in the development and plasticity of dendritic spines and synapses. Astrocytes can eliminate dendritic spines, induce synapse formation, and regulate neurotransmission and plasticity. Dendritic spine and synapse impairments are features of many neurological disorders, including autism spectrum disorder, schizophrenia, and Alzheimer's disease. In this review we will present evidence from multiple neurological disorders demonstrating that changes in astrocyte-synapse interaction contribute to the pathologies. Genomic analysis has connected altered astrocytic gene expression with synaptic deficits in a number of neurological disorders. Alterations in astrocyte-secreted factors have been implicated in the neuronal morphology and synaptic changes seen in neurodevelopmental disorders, while alteration in astrocytic glutamate uptake is a core feature of multiple neurodegenerative disorders. This evidence clearly demonstrates that maintaining astrocyte-synapse interaction is crucial for normal central nervous system functioning. Obtaining a better understanding of the role of astrocytes at synapses in health and disease will provide a new avenue for future therapeutic targeting.

Keywords: astrocyte; disease; synapse.

Figure 1. Astrocytes in synaptogenesis

A, astrocytes induce synapse formation by secreting factors such as TSP1/2, which binds to α2δ1 and neuroligin to induce structural synapse formation, and Gpc4/6, which recruits GluA1‐containing AMPA receptors to the synapse. B, there is strong evidence through co‐culture experiments that astrocyte secreted protein factors play a role in many neurodevelopmental disorders. In Down's syndrome, for example, it has been found that astrocytes secrete lower levels of TSP‐1, which may lead to changes in the structure of the synapse, though the exact mechanism of this action is not yet known.

Figure 2. The role of astrocytes in glutamate uptake

A, glutamate in the extracellular space is taken up by astrocytes through GLT‐1 and GLAST, whose expression in astrocytes can be upregulated by glutamate. The conversion of glutamate into glutamine is catalysed by glutamine synthetase (GS). Glutamine is transported back to the presynaptic neuron to be converted back to glutamate. B, this mechanism is impaired in various CNS disorders, such as RTT, FXS, stroke, AD and addiction. The excess glutamate can activate extrasynaptic NMDARs, leading to activation of excitotoxic pathways that cause synaptic loss and eventual cell death.