New Research Furthers Understanding of Synapse Formation―A Process Sometimes Disturbed in Schizophrenia

Joris de Wit, Ph.D. - Brain and behavior research expert on mental illness
Joris de Wit, Ph.D.

Joris de Wit, Ph.D., a 2009 NARSAD Young Investigator Grantee, has made an important discovery about how some of the trillions of communications links (or “synapses”) between neurons―nerve cells in the brain―take shape. This process, called synaptogenesis by scientists, is one of the fundamental things that makes it possible for us, and for all creatures with brains, to perceive, to think, to make decisions and judgments.

We have known for some years that the process of forming synapses is something like a handshake: sticky molecules on either side of the tiny gap between the branching dendrites and axons that shoot out from neurons in turn attract other molecules, which form complexes that form bridges, or handshakes, between two cells. Once forged, the synaptic bridge can carry across electrochemical signals that are the brain’s way of exchanging information.

Dr. de Wit, recently of the University of California, San Diego (UCSD) and now at the VIB Center for the Biology of Disease in Belgium, studied synapse formation with an eye to its undoing in illnesses including schizophrenia. He has now published a new paper online, August 1st, in the journal Neuron, along with a team that includes 2002 NARSAD Independent Investigator Grantee Anirvan Ghosh, of UCSD. Using a machine called a mass spectrometer, which enables scientists to figure out the components in a sample of tissue or cells by their characteristic molecular signatures, Drs. de Wit, Ghosh and colleagues discovered what happens when synapses form between so-called excitatory nerve cells.

These excitatory cells constitute the vast majority of neurons in the brain, and are strongly represented by cells that respond to the neurotransmitter glutamate. The team’s discovery reveals that many excitatory synapses are formed when molecules of one of six variants of glypican (GPC4), and proteins called LRRTM4 (one type of “leucine-rich repeat protein”) achieve a molecular handshake.

It is an important discovery, in part because flaws in LRRTM proteins that act in synapse development have been linked with schizophrenia susceptibility. This new work offers new direction in the development of treatments to correct key molecular abnormalities in schizophrenia.

This study is being published back-to-back with a paper from the lab of Ann Marie Craig, Ph.D., at the University of British Columbia in Canada, with similar discoveries on glypicans and LRRTM4.