Astrocyte-neuron crosstalk in neurodevelopmental disorders

Abstract

A fundamental feature shared across neurodevelopmental disorders (NDDs) is the disruption of synaptic circuit formation and homeostasis. During early life, non-neuronal cells called astrocytes tightly regulate the establishment of circuits by controlling formation, remodeling, stabilization, and maturation of synapses. Concurrently, astrocytes mature to meet the evolving needs of the developing brain. Bidirectional astrocyte-neuron communication synchronizes astrocyte maturation with synapse development. An emerging body of evidence supports the hypothesis that in NDDs, deficits in astrocyte-neuron communication underlie errors in synaptic circuit development. Here we will review and discuss these findings, with the aim of inspiring future research and guiding translational studies.

Figure 1:. Developmental mechanisms of select NDD-linked genes in astrocytes.

(a-b) astrocytes mature concurrently with synapse formation and maturation in human (a) and mouse (b). (c) Sensory systems linked to astrocyte dysfunction in genetic mouse models of NDDs. (d) NDD-linked genes encode nuclear proteins (left) involved in developmental gene expression [16, 25, 26, 55], or transmembrane proteins [9, 56], secreted molecules [16, 17], and intracellular scaffolding proteins [23, 43], which localize to the perisynaptic astrocyte processes (PAPs) (right).

Figure 2:. Astrocyte regulation of fronto-striatal circuit development

(a) orbito-frontal cortex (pink) and anterior cingulate cortex (yellow) each project to striatum (teal), where they regulate repetitive and motivational behaviors. (b) Astrocytes regulate excitatory synaptogenesis in the anterior cingulate cortex (ACC) via thrombospondin (Tsp1/2) secretion, and Tsp1/2 deletion reduces effort exertion in a high-effort task [40]. (c-d) Striatal astrocytes control repetitive and perseverative behaviors via their own structural elaboration, as in the Sapap3 KO mouse (c), where the actin cytoskeleton is dysregulated [43], and via modulation of extracellular neurotransmitters (d), as in the Crym cKO mouse [42].