Astrocyte regulation of synaptic glutamate receptors

Neurons in the brain are connected by billions of synaptic connections, the points of communication between neurons. These connections are critical to the function of the central nervous system, allowing our sensory, motor and cognitive systems to interact. This study investigates the molecular pathways that lead to synapse formation and strengthening in the developing brain, with a particular focus on signaling interactions between neurons and a class of glial cell, the astrocyte.

HFSP Long-Term Fellow Nicola Allen and colleagues
authored on Fri, 25 May 2012

Astrocytes constitute half of the cells in the brain, and astrocyte processes surround the majority of neuronal synapses, thus placing them in an ideal location to be actively involved in synapse formation, synapse maintenance and the modulation of synaptic transmission. Indeed, few functional synapses form between developing neurons in the absence of astrocytes, with astrocytes profoundly increasing the number of functional synapses that form, however the molecular mechanism responsible is not known. In this study we identify glypicans 4 and 6 as astrocyte-secreted signals that are sufficient to induce functional synaptic connections, which is achieved by recruiting AMPA glutamate receptors to the surface of neurons and clustering them at excitatory synaptic sites. Glypican-induced glutamate receptor clustering is sufficient to induce functional synapses between neurons, and removal of glypicans from astrocytes significantly reduces their ability to induce postsynaptic activity in neurons. Glypican 4 and 6 are expressed by astrocytes in vivo in the developing brain, with an enrichment of glypican 4 in the hippocampus and glypican 6 in the cerebellum. Glypican 4-deficient mice have defective excitatory synapse formation in the developing hippocampus, manifested as weaker synaptic connections due to reduced recruitment of AMPARs to synapses. Thus glypicans constitute a novel family of astrocyte-derived molecules that are necessary and sufficient to promote glutamate receptor clustering and induce the formation of post-synaptically functioning CNS synapses.

Reference

Astrocyte glypicans 4 and 6 promote formation of excitatory synapses via GluA1 AMPA receptors. Allen NJ, Bennett ML, Foo LC, Wang GX, Chakraborty C, Smith SJ, Barres BA. (2012) Nature, DOI: 10.1038/nature11059.

Nature link