New paper decodes crucial component in brain signal processing

A new paper from our lab published in the current issue of Neuron presents surprising information about how the human brain processes electrical and chemical signals. In a collaboration between the Charité lab and our former lab at Baylor College of Medicine in Texas, we demonstrate a mechanism by which the brain regulates synaptic strength, with vesicular glutamate transporters (VGLUTs) and the protein endophilin playing a key role. The discovery goes a long way towards explaining the diversity of synaptic function.

The central nervous system processes a large variety of information, including sensory processing and motor control, body homeostasis, emotions, and higher cognitive functions, within hundreds of anatomically and functionally distinct circuits. To accomplish this diversity, the neurons and synapses underlying these circuits employ a large set of tools including variation in neuronal morphology, synaptic connectivity, electrical processing within the neuron, and synaptic function. Presynaptic release probabilities contribute significantly to the functional diversity of synapses. They determine both the initial reliability of a synaptic connection and the short-term plasticity characteristics, as low-release probability synapses show facilitation, while high-release probability synapses tend to depress during action potential trains. The molecular mechanisms for the diversity of release probability are practically unknown.

Our new paper demonstrates a molecular mechanism of regulation of release probability that contributes to the functional diversity of different synapse populations. We identify endophilin A1 as a positive regulator of release probability and show how differential expression of VGLUT isoforms in neurons interact with endophilin A1 to shape the synaptic response. We propose the following model for the VGLUT isoforms’ regulation of release probability (see figure). The model shows that endophilin dimerizes and binds to synaptic vesicle membranes to achieve an active state that enhances release efficiency. VGLUT2-containing vesicles (top left) have high levels of active endophilin and high-release probability, while VGLUT1-containing vesicles (top right) have lower levels of active endophilin because of the inhibitory actions of VGLUT1. Overexpression of endophilin (bottom left) overwhelms the available VGLUT1 molecules and raises the level of active endophilin and the probability of vesicle release. Knockdown of endophilin (bottom right) severely decreases levels of active endophilin and the probability of vesicle release.

The classical role of VGLUTs is to fill vesicles with glutamate, and therefore the additional role in regulating release probability is surprising. Although previous research had shown that the distribution of VGLUT1 and VGLUT2 overlaps with that of synapses with different reliability, it was difficult to imagine how a vesicular neurotransmitter transporter might cause synapses to release glutamatergic vesicles with different probability. Our research provided us with a molecular explanation for the correlation between VGLUT expression and release probability.

Previous studies have shown that VGLUT levels are endogenously and bidirectionally regulated during development, in disease states, with pharmacological manipulation, and according to circadian rhythms. Our data suggest these alterations would be accompanied by changes in neuronal firing patterns and perhaps circuit behavior. For example, differences between VGLUT1 and VGLUT2/3 could be important during development, where the early, transient expression of VGLUT2 and VGLUT3 in neurons that later express VGLUT1 could increase the chance of glutamate release at synapses that may contain fewer synaptic vesicles than mature synapses. It is possible that neurons or networks of neurons actively use specific VGLUT isoform expression to regulate the efficiency of glutamate release.

Our results also led us to speculate the mechanism by which endophilin promotes endocytosis and enhances release probability are one and the same and that it acts at the step of vesicle retrieval from the plasma membrane to form vesicles that have an intrinsically higher release probability. This could be accomplished by altering the curvature of synaptic vesicles, altering the timing of membrane scission, or altering the internalization of endocytic cargo.

We now plan to explain how the nervous system uses the different VGLUTs in more detail, and investigate the pathophysiological relevance of VGLUTs.

Weston et al., Interplay between VGLUT Isoforms and Endophilin A1 Regulates Neurotransmitter Release and Short-Term Plasticity, Neuron (2011), doi:10.1016/j.neuron.2011.02.002

Link to the abstract (including video):