Duke researcher Cagla Eroglu, PhD and her colleagues have identified a key protein receptor in the brain which regulates development of important connections in the brain. A new research paper published in the Journal of Cell Biology explains how this molecule plays a pivotal part in brain development. Chris Risher, faculty member at Marshall University and a former Postdoctoral Fellow in the Eroglu lab, was the paper’s primary author. Risher says, “this work provides new insight into the development of aberrant synaptic circuitry in conditions like autism, epilepsy, and other neurological conditions.”
The brain is a highly complex organ that enables us to think, remember, move, and perform simple to complicated tasks. These tasks use brain circuits that are made up of connections between cells called neurons. Neurons contact each other at sites known as synapses, and the human brain is estimated to contain trillions of these connections. The way that synapses form in the brain, and how faulty connectivity may lead to brain dysfunction, are still largely unanswered questions in neurobiology.
In the last decade and a half, research has pointed to a non-neuronal basis for regulating synaptic connectivity. Star-shaped “connector” cells known as astrocytes, which far outnumber neurons in the brain, secrete factors that modulate the timing and extent of synapse formation. One of these factors, an extracellular protein called thrombospondin (TSP), was previously shown to promote synapse formation via a receptor, α2δ-1. But the mechanism of synapse formation was not yet known.
Risher used a technique called three-dimensional electron microscopy to study synapse formation in mice brains. In this paper, they show that that α2δ-1 is required for the structural maturation of synapses. They determined that a molecule produced by α2δ-1 stimulates structural maturation of neurons. Mice neurons that lacked α2δ-1 or the molecule it produces remained in an immature state. When they restored the receptor and its functions, the synaptic deficiencies were reversed.
This paper lays the groundwork for future therapies and treatments targeting conditions that are caused by deficient astrocyte-to-neuron signaling. One such drug, the FDA-approved drug gabapentin (Neurontin) is used to treat a variety of neurological conditions and works by targeting TSP and α2δ-1. In humans, defects in TSP, α2δ-1 and their signaling partners have been implicated in autism, epilepsy, and other neurological conditions.
Citation: Thrombospondin receptor α2δ-1 promotes synaptogenesis and spinogenesis via postsynaptic Rac1. Risher, Kim, et.al., Journal of Cell Biology DOI: 10.1083/jcb.201802057 | Published July 27, 2018