The proteins that join neurons together at the synapse do more than just act like glue. Synaptic adhesion proteins are known to affect the activity of neurotransmitters, weaken or strengthen synaptic connections, or direct where synapses form. Faulty adhesion proteins have even been implicated in conditions such as autism, schizophrenia, and bipolar disorder.
One longstanding idea about these molecules also puts them at the center of synapse identity—with specific configurations of adhesion molecules directing how each connection looks and operates. This view gains traction in a new study by researchers in Belgium, published in Neuron.
The researchers observed different combinations of molecules at two synaptic locations on a single neuron in rats, and showed that each has a particular effect on how the synapse works. Senior author Joris de Wit of the VIB Center for Brain & Disease Research in Leuven likens the proteins to “little molecular Lego blocks that can plug into a synapse, and that change the properties of the synapse.”
And the human brain has a lot of synapses—between 1,000 and 10,000 on each of its 80 billion or so neurons. “Every connection has its own peculiar functional properties,” says de Wit.
Anna Schröder, a graduate student in de Wit’s lab, and their colleagues focused on adhesion proteins in the leucine-rich repeat (LRR)-containing family. Dozens of members of this family are expressed in distinctive patterns in the brain, suggesting that they might have distinct roles. And this is just what the researchers’ data suggest.
They looked at how three LRR proteins operate in the CA1 pyramidal neurons of the hippocampus, a brain region involved in learning and memory. As the long CA1 neurons stretch through the hippocampus, they pass through several tissue layers, forming synapses in each layer that receive input from different brain regions. “It’s a very ordered structure,” says de Wit.
The researchers found that at one layer—receiving inputs mainly from other hippocampal neurons—the CA1 neuron expressed all three LRR proteins at synapses. But at a second layer—receiving inputs mainly from the frontal lobes—only two LRR proteins were expressed. By knocking out the proteins singly or in combination with RNA-mediated interference, and by studying the morphology of the synapse and its electrophysiology, they could also see that the absence of specific proteins had differing effects.
One protein, for instance, influenced the number of dendritic spines, button-like structures where most of the synaptic contacts are situated—knocking it out also muffled the electrophysiological response to signals impinging on CA1. The two other LRR proteins also affected the distribution of vesicles at the synapse poised to release neurotransmitters, although in opposing ways.
Context also counted. One of the proteins took on a completely new role in a second CA1 layer, seeming to alter the density of a receptor involved in neurotransmission. “These proteins are highly specialized,” says de Wit.
The study is “well executed,” says Philip Washbourne, an associate professor at the Institute of Neuroscience at the University of Oregon. But he adds that the “holy grail is basically finding a synaptic code,” one in which specific combinations of adhesion molecules define the properties of a synapse. The findings chip away at this idea, says Washbourne, but are not conclusive—for instance, some of the effects of knocking out the LRR proteins were subtle, he notes.
Subtle effects are in line with previous knock-out studies of other adhesion molecules families, though. It seems that some adhesion molecules may have some redundancy, compensating for one another. And each may have only a relatively minor role on its own, says de Wit.
Subtle effects also make sense given that these three LRR adhesion molecules are associated with neuropsychiatric disorders, and that the brain often functions well much of the time in people with such conditions, says de Wit. “These proteins are really fine tuners,” he says. “They fine tune the way a synapse looks and functions.”