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GABA signaling prunes back copious ‘provisional’ synapses during neural circuit assembly

Early in cortical development, the neurotransmitter GABA triggers a pruning back of incompatible preliminary synaptic connections

Cold Spring Harbor, NY — Quite early in its development, the mammalian brain has all the raw materials on hand to forge complex neural networks.  But forming the connections that make these intricate networks so exquisitely functional is a process that occurs one synapse at a time.  An important question for neuroscience has been: how exactly do stable synapses form?  How do nerve cells of particular types know which of their cortical neighbors to “synapse” with, and which to leave out of their emerging networks?

Early in cortical development, when GABA synthesis was blocked in inhibitory basket cell neurons, axons and preliminary synaptic connections with nearby pyramidal excitatory neurons were overabundant (row f = control; g and h show overgrowth). In col. 3, right, structures called boutons make contact (arrows) with pyramidal cells; normally, GABA transmission triggers pruning of clusters seen in g3 and h3.

Neuroscientist Z. Josh Huang, a professor at Cold Spring Harbor Laboratory, and his laboratory team spearheaded by graduate student Xiaoyun Wu tomorrow publish a finding in The Journal of Neuroscience that Huang says surprised them, even after years of work on this problem.

In emerging networks being established by GABA interneurons—inhibitory brain cells named for the neurotransmitting chemical, gamma aminobutyric acid, that they release—Huang’s team found strong evidence that the “default state” is for the cell to make tentative connections promiscuously, with almost every available partner.  That much they had anticipated.

The unexpected observation was that GABA proved not to be involved in the initial formation of these tentative or “test” synapses, but rather in the essential process of pruning them back, later, after they had been formed.  The net effect of provisional synapse formation and rapid subsequent pruning, Huang says, is “a bit like speed dating.”

Huang explains that there are two known mechanisms at work in synapse formation.  One is genetic, and involves the recruitment of highly specific neural cell adhesion molecules to the site of a tentative synaptic connection.  These adhesion molecules, in lock-and-key fashion, form a physical but reversible glue-like bond between, say, a tentative synaptic projection from one GABA cell’s axon and a receiving structure located across a tiny space on a neighboring cell body axon or dendritic filament emanating from another nerve cell.  Last year, Huang’s team became the first to observe how this process is regulated in living cortical circuits.

In their newly published research, they demonstrate in living basket cell interneurons—an important and prevalent subtype of GABA neuron—that a total blockade of GABA synthesis has no impact on the appearance of the many tentative synapses.  “This state of preliminary contact appears to be the default state in these neurons,” Huang says.

“GABA turns out to be a kind of discriminatory mechanism.  As in speed-dating, in the end you want to form connections with the right partner. And you don’t want to spend too much time or too much of your available resources checking each possibility out.”

Interestingly, virtually all possibilities for matches—in this case in terms of physical availability, i.e., proximity—are seriously considered.  GABA’s surprising role is to serve as a trigger of the mechanism that swiftly eliminates incompatible contacts.  Incompatibility in this context can mean biochemical or functional incongruity.

What is not yet understood, says Huang, is the nature of the pruning mechanism that GABA triggers.  “There is some other signaling mechanism ‘downstream,’ so to speak, of GABA’s triggering that performs the pruning.  One possibility is that it is linked to GABA receptors.  But we do not yet know.”

Elucidating that detail is the next scientific objective of the team.

Written By: Peter Tarr, Senior Science Writer | publicaffairs@cshl.edu | 516-367-8455


Funding

This research was supported by a grant from the Harold and Leila Mathers Foundation and by the Robertson Neuroscience Fund at Cold Spring Harbor Laboratory.

Citation

“GABA Signaling Promotes Synapse Elimination and Axon Pruning in Developing Cortical Inhibitory Interneurons” appears January 4, 2012 in The Journal of Neuroscience. The authors are: Xiaoyun Wu, Yu Fu, Graham Knott, Jiangteng Lu, Graziella Di Cristo and Z. Josh Huang.  The paper will be available online January 4 at doi:10.1523/jneurosci.3189-11.2012.

About Cold Spring Harbor Laboratory

Founded in 1890, Cold Spring Harbor Laboratory has shaped contemporary biomedical research and education with programs in cancer, neuroscience, plant biology and quantitative biology. Home to eight Nobel Prize winners, the private, not-for-profit Laboratory employs 1,100 people including 600 scientists, students and technicians. The Meetings & Courses Program annually hosts more than 12,000 scientists. The Laboratory’s education arm also includes an academic publishing house, a graduate school and the DNA Learning Center with programs for middle and high school students and teachers. For more information, visit www.cshl.edu