CLICK ON weeks 0 - 40 and follow along every 2 weeks of fetal development
LRP4 molecule critical to synapse
Many neurological diseases result from malfunctions in synapses — that point of contact where sensory information traveling along a neuron becomes stored information in the brain. From finger-tip to brain, there is a careful balance between excitatory synapses which move signals along neurons to the brain, and inhibitory synapses that slow down signals involved in brain responses. When the excitatory—inhibitory balance becomes unbalanced, normal processing of information malfunctions, as seen in conditions like epilepsy.
Now, research at Thomas Jefferson University in Center City, Philadelphia, Pennsylvania, has discovered how one molecule might play a role in maintaining that delicate balance. Results from research conducted in a joint project between Thomas Jefferson and the Howard Hughes Medical Institute at Stanford University, the Wellcome Trust Institute, London, United Kingdom, and the Max Planck Institute, Munich, Germany, were published in the journal eLife.
Timothy Mosca PhD, Assistant Professor in the Department of Neuroscience at the Vickie and Jack Farber Institute for Neuroscience at Thomas Jefferson University, discovered that a molecule called LRP4, is important in creating excitatory synapses — those keeping a message passing from one neuron to the next. When researchers knocked out the LRP4 gene in fruit flies, they saw a 40 percent loss of excitatory synaptic connections in the brain, but no loss of inhibitory synapses, suggesting the LRP4 molecule is specific to only excitatory synapse.
Researchers used a new technology called expansion microscopy to get a better view of fruit fly neurons. Mosca: "In most cases, if you want to see very small things with better resolution, you get a better microscope. The other option is to make the small things bigger." By infusing neurons under study with the chemical used in diapers to absorb moisture, scientists were able to make the neurons and their synapses enlarge enough to be seen more clearly.
"Most molecules involved in synapse biology are vital to both excitatory and inhibitory neurons. The idea that we now have a molecule that appears to be specific to excitatory synapses suggests there is probably a parallel molecule that exists that helps form inhibitory ones, that we just haven't found yet."
A better understanding of the unique biology of excitatory and inhibitory synapses may go a long way in helping researchers untangle the many diseases thought to be related to synapse dysfunction including autism and schizophrenia.
Precise coordination of synaptic connections ensures proper information flow within circuits. The activity of presynaptic organizing molecules signaling to downstream pathways is essential for such coordination, though such entities remain incompletely known. We show that LRP4, a conserved transmembrane protein known for its postsynaptic roles, functions presynaptically as an organizing molecule. In the Drosophila brain, LRP4 localizes to the nerve terminals at or near active zones. Loss of presynaptic LRP4 reduces excitatory (not inhibitory) synapse number, impairs active zone architecture, and abolishes olfactory attraction - the latter of which can be suppressed by reducing presynaptic GABAB receptors. LRP4 overexpression increases synapse number in excitatory and inhibitory neurons, suggesting an instructive role and a common downstream synapse addition pathway. Mechanistically, LRP4 functions via the conserved kinase SRPK79D to ensure normal synapse number and behavior. This highlights a presynaptic function for LRP4, enabling deeper understanding of how synapse organization is coordinated.
Article reference: T.J. Mosca et al., "Presynaptic LRP4 Promotes Synapse Number and Function of Excitatory CNS Neurons," eLife, 6:e27347, 2017.
This work was supported by grants from the National Institutes of Health, NIH K99/R00-DC013059 and R01 DC-005982. Author Liqun Luo is an Investigator of the Howard Hughes Medical Institute.
Return to top of page
LRP4 is the Neurotransmitter Molecule identified in this close up
of the moment of synapse transmission.
Image credit: Wikipedia