The Chemical Attraction Underlying Synaptic Diversity

Cell adhesion molecules regulate the formation and function of specialized structures involved in neuron-to-neuron communication in the brain.

A type of cell adhesion molecule called netrin-G tethers discrete synaptic circuits together in the brain to regulate neural circuit function, finds an international team of researchers led by Shigeyoshi Itohara from the RIKEN Brain Science Institute. This finding offers new insight into how diversity is created in neural circuits with potential relevance to neurological disorders such as schizophrenia.

The transmission of information in the brain relies on the precise arrangement of connections between neurons. The formation of these connections, called synapses, is controlled by cell adhesion molecules expressed on the neuron surface. Netrin-G1 and netrin-G2 are two such molecules, which bind to their specific binding partners, netrin-G1 ligand (NGL1) and netrin-G2 ligand (NGL2).

The researchers used immunoelectron microscopy techniques to observe synapses in the hippocampus, where netrin-G1 and netrin-G2 had previously been found in distinct neuronal populations. This investigation revealed that netrin-G proteins occur on the presynaptic membrane, while NGLs occur on the postsynaptic membrane. Studying mice missing just one of these molecules, Itohara’s team discovered that mice lacking either of the receptors had reduced levels of netrin-G at the synapse, suggesting that netrin-Gs and NGLs were mutually required to keep the respective molecules at the synapses.

The loss of netrin-G or NGL led to changes in synaptic functions in a circuit-specific manner. For example, the strengthening of a certain neuronal circuit by the application of a long train of stimulatory pulses—a type of synaptic plasticity thought to play a role in learning—was suppressed in mice deficient in netrin-G1 or NGL1, but occurred normally in mice deficient in netrin-G2 or NGL2. Yet in another synaptic circuit, this synaptic ‘potentiation’ was enhanced in mice deficient in netrin-G2 or NGL2, but not in mice deficient in netrin-G1 or NGL1.

This image shows a cell adhesion molecule called netrin-G regulates the formation and function of specialized structures involved in inter-neuron communication in the brain.
A cell adhesion molecule called netrin-G regulates the formation and function of specialized structures involved in inter-neuron communication in the brain. Image credit: H. Matsukawa et al..

Overall, the results suggest that particular netrin-G–NGL pairings are required across the synapse to maintain normal synaptic function in a circuit-specific manner. In other words, the formation of synaptic structures and the diversity of their functions are mediated, at least in part, by the expression of various cell adhesion molecules and their receptors in different neurons within a particular brain structure and neural network.

“Human genetic studies have suggested the involvement of netrin-G1 and netrin-G2 in various neurological diseases, including schizophrenia and bipolar disorder,” explains Itohara. “The interactions between netrin-G and its receptors determine the circuit-specific characteristics of synapses and might even underlie the elaboration of higher brain function in humans,” he says.

About this neuroethics research

Source: RIKEN
Image Source: The image is credited to H. Matsukawa et al.
Original Research: Abstract for “Netrin-G/NGL Complexes Encode Functional Synaptic Diversification” by Hiroshi Matsukawa, Sachiko Akiyoshi-Nishimura, Qi Zhang, Rafael Luján, Kazuhiko Yamaguchi, Hiromichi Goto, Kunio Yaguchi, Tsutomu Hashikawa, Chie Sano, Ryuichi Shigemoto, Toshiaki Nakashiba, and Shigeyoshi Itohara in Journal of Neuroscience. Published online May 25 2015 doi:10.1523/JNEUROSCI.1141-14.2014


Abstract

Netrin-G/NGL Complexes Encode Functional Synaptic Diversification

Synaptic cell adhesion molecules are increasingly gaining attention for conferring specific properties to individual synapses. Netrin-G1 and netrin-G2 are trans-synaptic adhesion molecules that distribute on distinct axons, and their presence restricts the expression of their cognate receptors, NGL1 and NGL2, respectively, to specific subdendritic segments of target neurons. However, the neural circuits and functional roles of netrin-G isoform complexes remain unclear. Here, we use netrin-G-KO and NGL-KO mice to reveal that netrin-G1/NGL1 and netrin-G2/NGL2 interactions specify excitatory synapses in independent hippocampal pathways. In the hippocampal CA1 area, netrin-G1/NGL1 and netrin-G2/NGL2 were expressed in the temporoammonic and Schaffer collateral pathways, respectively. The lack of presynaptic netrin-Gs led to the dispersion of NGLs from postsynaptic membranes. In accord, netrin-G mutant synapses displayed opposing phenotypes in long-term and short-term plasticity through discrete biochemical pathways. The plasticity phenotypes in netrin-G-KOs were phenocopied in NGL-KOs, with a corresponding loss of netrin-Gs from presynaptic membranes. Our findings show that netrin-G/NGL interactions differentially control synaptic plasticity in distinct circuits via retrograde signaling mechanisms and explain how synaptic inputs are diversified to control neuronal activity.

“Netrin-G/NGL Complexes Encode Functional Synaptic Diversification” by Hiroshi Matsukawa, Sachiko Akiyoshi-Nishimura, Qi Zhang, Rafael Luján, Kazuhiko Yamaguchi, Hiromichi Goto, Kunio Yaguchi, Tsutomu Hashikawa, Chie Sano, Ryuichi Shigemoto, Toshiaki Nakashiba, and Shigeyoshi Itohara in Journal of Neuroscience. Published online May 25 2015 doi:10.1523/JNEUROSCI.1141-14.2014

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