Making the right connections

Scientists uncover the essential role of postsynaptic NMDA receptors in developmental refinement of excitatory synapses.

Soon after birth, mammals’ brains undergo significant development and change. Initially, large numbers of weak synapses form between neurons. Then, in response to stimuli, the synaptic connections are refined—some synapses are strengthened and others eliminated, or pruned. The early post-natal synaptic refinement process is necessary for neural circuit formation and behavioral development, but it is still not well understood.

In a paper published in the Proceedings of the National Academy of Sciences, JAX Associate Professor Zhong-wei Zhang establishes the necessity of a specific neurotransmitter receptor in the process. Glutamate serves as the neurotransmitter in most of the synapses, and the post-synaptic glutamate receptor, known as NMDAR (N-methyl-D-aspartate receptor), was previously known to play an important role in neural circuit development. Preliminary research has implicated the importance of NMDARs in early synaptic refinement as well, but it remained unclear if it played direct or indirect role.

Zhang and colleagues focused on a brain region where synapse strengthening and pruning can be monitored and quantified with relative ease. Using mice with mosaic deletion of NMDARs—the receptors were deleted in some neurons but present in others within the same region—the researchers showed that the refinement process was disrupted in the absence of NMDARs. At the same time, neighboring neurons with the receptors proceeded through normal synaptic strengthening and pruning, clearly establishing the necessity of NMDARs for synaptic refinement.

There has been extensive research into synaptic strengthening, and most of these studies indicate that the presence of NMDARs may support the recruitment of larger numbers of another kind of glutamate receptor to strengthen the synaptic connections. How NMDARs regulate the pruning process remains largely unknown, however.

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Dr. Zhong-wei ZhangZhong-wei Zhang is investigating the mutation that causes Rett syndrome and the role of the normal protein, MeCP2, in brain development.

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Read the paper

Liu et al.: Essential role of postsynaptic NMDA receptors in developmental refinement of excitatory synapses. Proceedings of the National Academy of Sciences.

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