Synaptic contacts are believed to provide the morphological basis for information processing in the brain. Joachim Kirsch and Heinrich Betz from the Max Planck Institute for Brain Research (Frankfurt/Germany) report in "nature" (April 16) that neurotransmitter-triggered activity of the postsynaptic cell is a key signal for synapse formation.
Nerve cells communicate via specialized cell-cell contacts, the so-called synapses. Upon stimulation of the presynaptic cell, neurotransmitter is released from its nerve endings. The released transmitter molecules diffuse to the adjacent nerve cell and activate specific receptor proteins that are highly concentrated within the membrane segment underlying the presynaptic nerve terminal, the postsynaptic membrane proper. By culturing embryonic spinal cord neurons and pharmacological approaches Joachim Kirsch and Heinrich Betz, both from the Max Planck Institute for Brain Research (Frankfurt/Germany), now (nature, 392, 717-720) show that neurotransmitter-induced activity of the postsynaptic nerve cell is required for inducing the aggregation of receptors for the amino acid glycine, the major inhibitory neurotransmitter in the spinal cord.
Already in 1993, these scientists had reported (also in "nature") that the accumulation of the glycine receptor-associated cytoplasmic protein gephyrin at developing postsynaptic sites preceeds clustering of the glycine receptor, and that the expression of this peripheral membrane protein is essential for the formation of postsynaptic glycine receptor aggregates. It remained enigmatic, however, which signals instruct a cytoplasmic protein about the presence or absence of an apposing glycinergic nerve terminal. By paralyzing cultured spinal neurons with tetrodotoxin Kirsch and Betz now found that electrical activity is required for glycine receptor clustering. In a second step, they investigated whether electrical activity induced by activation of the glycine receptor itself might be an important component in this process. Therefore, neuronal cultures were treated with the highly selective glycine receptor antagonist strychnine. This treatment abolished both gephyrin and glycine receptor clustering in a dose-dependent manner. Knowing that glycine receptor activation in embryonic neurons can result in membrane depolarization and the opening of voltage-gated calcium channels, spinal cord cultures were treated with calcium channel antagonists and again, receptor clustering was strongly reduced.
The data suggest the following model for postsynaptic membrane formation: Initially glycine receptors are diffusely distributed in the neuronal plasma membrane. Whenever receptors, encounter freely diffusing an active nerve terminal releasing the appropriate neurotransmitter, namely glycine, they open and the resulting ion flux generates a local change in membrane potential. This induces the opening of voltage-gated calcium channels. The resulting calcium influx triggers a second messenger cascade which together with additional presynaptic effectors causes the aggregation of gephyrin beneath the activated plasmamembrane. The aggregates of this peripheral membrane protein then act as a diffusion trap for additional glycine receptor polypeptides. This passive mechanism concentrates the receptors at the developing postsynaptic site.
In the forties, Donald Hebb postulated that the coincident activity of both pre- and postsynaptic nerve cells constitutes the electrophysiological correlate of learning and memory. The findings reported by Kirsch and Betz in nature 392, 717-720 indicate that adequate neuronal activity is also a prerequisite for synapse formation. These similarities in the molecular events underlying learning and memory and those operating during synaptogenesis are consistent with studies showing that experience modifies neuronal circuitries both during development and in adulthood.
Journal
Nature