The role of astrocyte-mediated plasticity in neural circuit development and function

Abstract

Neuronal networks are capable of undergoing rapid structural and functional changes called plasticity, which are essential for shaping circuit function during nervous system development. These changes range from short-term modifications on the order of milliseconds, to long-term rearrangement of neural architecture that could last for the lifetime of the organism. Neural plasticity is most prominent during development, yet also plays a critical role during memory formation, behavior, and disease. Therefore, it is essential to define and characterize the mechanisms underlying the onset, duration, and form of plasticity. Astrocytes, the most numerous glial cell type in the human nervous system, are integral elements of synapses and are components of a glial network that can coordinate neural activity at a circuit-wide level. Moreover, their arrival to the CNS during late embryogenesis correlates to the onset of sensory-evoked activity, making them an interesting target for circuit plasticity studies. Technological advancements in the last decade have uncovered astrocytes as prominent regulators of circuit assembly and function. Here, we provide a brief historical perspective on our understanding of astrocytes in the nervous system, and review the latest advances on the role of astroglia in regulating circuit plasticity and function during nervous system development and homeostasis.

Keywords: Astrocyte; Circuits; Gap junction; Hebbian plasticity; Homeostatic plasticity; Synapses.

Fig. 1

Astrocytes locally support neuronal synapses. a Light microscopy image of single astrocyte (cyan) contacting the pre-synaptic membrane of the Drosophila A18b neuron (magenta), with pre-synapses highlighted in the inset (yellow). First instar larva. Genotype: A18b (94E10-lexA; 8xlexAop-2xBrp-short::cherry; lexAop-myr::GFP), astrocyte (25h07-gal4; hs-FLPG5;; 10xUAS(FRT.stop)myr::smGdP-HA, 10xUAS(FRT.stop)myr::smGdP-V5, 10xUAS-(FRT.stop)myr::smGdP-FLAG). Scale bar, 200 nm. b TEM image showing a single astrocyte (cyan) contacting the pre-synaptic membrane of the A18b neuron (magenta), and the post-synaptic membrane of an A27a neuron (green) with synapses highlighted (yellow asterisks). Genotype: wild type. First instar larva. Scale bar, 500 nm

Fig. 2

Select mechanisms for astrocyte-induced plasticity. a Hebbian plasticity. Recruitment of NMDA receptors is mediated by astrocyte-derived Hevin and the cell adhesion molecules Neuroligin-1 (NL1) and Neurexin-1 (Nrxn1) during the ocular dominance plasticity critical period. Astrocyte chondroitin sulfate proteoglycans (CSPGs) and SPARC stabilize AMPA postsynaptic receptors. Astrocyte gap junction proteins Connexins 30 and 43 regulate metabolite transport through monocarboxylate transporters (MCT1/2) between astrocytes and neurons in an activity-dependent manner to facilitate plasticity. b Homeostatic plasticity. Astrocyte-derived SPARC limits aggregation of AMPA receptors to facilitate synaptic scaling in response to chronic silencing. Additionally, receptors and transporters located in the astrocytic membrane monitor neuronal Ca²⁺ transients and release of neurotransmitters, resulting in gliotransmitter release. c Structural-homeostatic plasticity. Astrocyte-secreted Chrdl1 restricts neuronal plasticity by directly switching postsynaptic neurotransmitter receptor identity. Astrocyte-derived Neuroligin (NL) binds dendritic Neurexin (Nrxn) to mediate the closure of critical periods by stabilizing dendrite microtubule populations. Synapse elimination is driven by neuronal activity, and is regulated by astroglial MERTK and MEGF10. d Repeated excitatory postsynaptic potentials evoke more robust synaptic activity in potentiated circuits over time. Conversely, synapses targeted by long term depression display lower levels of excitability following stimulation. e Homeostatic mechanisms decrease the difference between synaptic input and output by bidirectionally adjusting the probability of transmitting an action potential postsynaptically

Fig. 3

Select mechanisms for astrocyte-modulated neuronal signaling. Top: Simple model circuit showing three linearly connected neurons (n) and associated astrocytes (a). at two synaptic (S) connections. Synapse 1: Influx of calcium into gap junction-coupled astrocytes via TRPA1 channels occurs in response to local neuronal activity. Elevation of astrocytic calcium causes astrocyte activation and release of gliotransmitters including D-serine, which induces NMDAR-dependent LTP. Synapse 2: Elevation of astrocytic calcium can also drive release of the gliotransmitters ATP and glutamate, which can stimulate pre-synaptic adenosine and metabotrophic glutamate (mGluR) receptors, respectively, to promote signaling of downstream neurons and drive the flow of information through the circuit