Balancing connections for proper brain function

June 22, 2012
Figure 1: Compared with the brains of normal animals (left), mice lacking the Slitrk3 gene (right) have a reduced density of inhibitory synapses in the hippocampus. Reproduced from Ref. 1 © 2012 Jun Aruga, RIKEN Brain Science Institute

Neuropsychiatric conditions such as autism, schizophrenia and epilepsy involve an imbalance between two types of synapses in the brain: excitatory synapses that release the neurotransmitter glutamate, and inhibitory synapses that release the neurotransmitter GABA. Little is known about the molecular mechanisms underlying development of inhibitory synapses, but a research team from Japan and Canada has reported that a molecular signal between adjacent neurons is required for the development of inhibitory synapses.

In earlier work, the researchers—led by Jun Aruga of the RIKEN Brain Science Institute, Wako, and Ann Marie Craig of the University of British Colombia, Vancouver—showed that a membrane protein called Slitrk2 organizes signaling molecules at synapses. They therefore tested whether five related proteins are involved in inhibitory synapse development. They cultured immature hippocampal with non-neural cells expressing each of the six Slitrk proteins. They found that Slitrk3, but not other Slitrk proteins, induced clustering of VGAT, a GABA transporter protein found only at inhibitory synapses.

The researchers also examined the localization of Slitrk3 by tagging it with yellow fluorescent protein and introducing it into cultured hippocampal cells. This revealed that Slitrk3 co-localizes in the dendrites of neurons with gephyrin, a scaffold protein found only in inhibitory synapses. They then blocked Slitrk3 synthesis, and found that it led to a significant reduction in the number of inhibitory synapses.

To confirm these findings, the researchers generated a strain of genetically engineered mice lacking the Slitrk3 gene. These animals had significantly fewer inhibitory synapses than normal animals (Fig. 1), and therefore impaired neurotransmission of GABA. They were also susceptible to epileptic seizures. From a screen for proteins that bind to Slitrk3, Aruga, Craig and colleagues identified the protein PTPδ as its only binding partner. Introduction of PTPδ fused to yellow fluorescent protein to cultured hippocampal neurons showed that it is expressed in neuronal dendrites and cell bodies, but not in axons. Blocking PTPδ synthesis prevented the induction of inhibitory synapses by the Slitrk3 protein.

These results demonstrated that the interaction between Slitrk3 on dendrites and PTPδ on axons of adjacent cells is required for the proper development of inhibitory synapses and for inhibitory neurotransmission in the brain.

“We are now examining whether the balance of excitatory and inhibitory synapses is affected by other members of the Slitrk protein family,” says Aruga. “It is possible that Slitrk3 and other Slitrk proteins are acting synergistically or antagonistically. We are also clarifying whether Slitrk3 is involved in any neurological disorders.”

Explore further: Learning mechanism of the adult brain revealed

More information: Takahashi, H., Katayama, K., Sohya, K., Miyamoto, H., Prasad, T., Matsumoto, Y., Ota, M., Yasuda, H., Tsumoto, T., Aruga, J. & Craig, A.M. Selective control of inhibitory synapse development by Slitrk3-PTPδ trans-synaptic interaction. Nature Neuroscience 15, 389–398 (2012). www.nature.com/neuro/journal/v … /n3/abs/nn.3040.html

Linhoff, M.W., Laurén, J., Cassidy, R.M., Dobie, F.A., Takahashi, H., Nygaard, H. B., Airaksinen, M.S., Strittmatter, S.M. & Craig, A.M. An unbiased expression screen for synaptogenic proteins identifies the LRRTM protein family as synaptic organizers. Neuron 5, 734–749 (2009). www.ncbi.nlm.nih.gov/pubmed/19285470

Related Stories

Learning mechanism of the adult brain revealed

April 26, 2012
They say you can't teach an old dog new tricks. Fortunately, this is not always true. Researchers at the Netherlands Institute for Neuroscience have now discovered how the adult brain can adapt to new situations. The Dutch ...

Excitation and inhibition remain balanced, even when the brain undergoes reorganization

September 7, 2011
Every second, the brain's nerve cells exchange many billions of synaptic impulses. Two kinds of synapses ensure that this flow of data is regulated: Excitatory synapses relay information from one cell to the next, while inhibitory ...

Recommended for you

Researchers find monkey brain structure that decides if viewed objects are new or unidentified

August 18, 2017
A team of researchers working at the University of Tokyo School of Medicine has found what they believe is the part of the monkey brain that decides if something that is being viewed is recognizable. In their paper published ...

Artificial neural networks decode brain activity during performed and imagined movements

August 18, 2017
Artificial intelligence has far outpaced human intelligence in certain tasks. Several groups from the Freiburg excellence cluster BrainLinks-BrainTools led by neuroscientist private lecturer Dr. Tonio Ball are showing how ...

Study of nervous system cells can help to understand degenerative diseases

August 18, 2017
The results of a new study show that many of the genes expressed by microglia differ between humans and mice, which are frequently used as animal models in research on Alzheimer's disease and other neurodegenerative disorders.

How whip-like cell appendages promote bodily fluid flow

August 18, 2017
Researchers at Nagoya University have identified a molecule that enables cell appendages called cilia to beat in a coordinated way to drive the flow of fluid around the brain; this prevents the accumulation of this fluid, ...

Researchers make surprising discovery about how neurons talk to each other

August 17, 2017
Researchers at the University of Pittsburgh have uncovered the mechanism by which neurons keep up with the demands of repeatedly sending signals to other neurons. The new findings, made in fruit flies and mice, challenge ...

Neurons involved in learning, memory preservation less stable, more flexible than once thought

August 17, 2017
The human brain has a region of cells responsible for linking sensory cues to actions and behaviors and cataloging the link as a memory. Cells that form these links have been deemed highly stable and fixed.

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.