Wrap Your Mind Around the Synapse — Just Try
After poring through scientific papers and articles, the complexity of synaptic transmission baffles me. For a neural signal to make it through the steps of packaging neurotransmitters, sending them across a gap, and then triggering a response inside the next neuron, seems needlessly complicated. Dozens of proteins and factors are involved at every synaptic crossing.
Why would evolution, or intelligent design, end up with such a method? It looks like a kludge. The power lines that engineers build do not operate that way. They keep continuous contact for the nonstop flow of electrons. It wouldn’t make sense at each power pole to convert the electricity to chemical energy and back again. Why does the body do it?
But one has to admit that it works very well, and extremely rapidly. Within milliseconds, a signal from your foot makes it to the brain and back again. On its way, that signal repeatedly undergoes the energy conversion at each synapse. Signals from the feet continuously traverse nearly two meters of nerve fibers packed with molecular machines and ion pumps, crossing synapses at each junction. It’s uncanny, but that’s what biophysicists and biochemists have found. Professors at UC Santa Barbara estimate that some neural signals can travel over 100 miles per hour!
As an avid hiker and backpacker, I have often crossed streams, walking across narrow logs over rushing water. I have leaped from rock to rock to get over a boulder pile, at each moment needing to decide where to place my feet, adjusting quickly if I feel the rock moving. The flow of information from eyes to brain to feet and back again, giving rapid and continuous feedback on my path, is something I am tremendously grateful for. Those synapses have given me invigorating experiences and have saved me from nasty falls uncountable times. The rapid, risky movements of gymnasts and parkour players and squirrels far exceed my exploits, but any of us who have walked irregular paths, up and down stairs, or quickly dodged a moving object have reason to be interested in how the body accomplishes rapid signaling through neurons. Now, cryo-electron microscopy has allowed scientists to peer deeper into the mysteries of the synapse.
Advancing Knowledge
The basic function of the synapse has been understood for many years. Neurotransmitter molecules, usually glutamate (the anion of the amino acid glutamic acid), are packaged into synaptic vesicles (SVs) with COPI proteins like birds in a cage. This process is elaborate in itself, as my article on coatomers described last year. Triggered by calcium ion bursts, the SVs bind to the membrane facing the cleft and release their neurotransmitters into the gap. The molecules bind to receptors on the receiving side, triggering another chain of ion channels that continue the signal down the neuron. The signal propagates all the way to the next synapse.
This much was known, but there were many questions. Biochemists have been limited in their ability to envision the details in the 20-nanometer synaptic cleft and adjacent neural receptors. In PNAS, Richard G. Held and colleagues from Stanford described how they observed synaptic vesicles at the nanoscopic scale by applying cryo-electron tomography after “slicing” synapses from the hippocampus with focused ion-beam milling. This gave them an unprecedented view of the positions of numerous proteins during movement of neurotransmitters across the synapse. Sure enough, the SVs look like little balls with protein tethers attached to guide them.
Zooming In
Jeremy S. Dittman of Cornell commented on the paper in PNAS. He summarized what happens in preparation for traversing the synapse:
Many of the big questions currently being explored by synaptic biologists are centered on the mechanistic details of the exocytic process and how the two sides of the synapse coordinate signal transmission with reception,briefly summarized as follows: On the presynaptic side, small neurotransmitter-filled synaptic vesicles (SVs) traffic to the cleft-facing electron-dense region of the plasma membrane termed an “active zone” (AZ) where they become tightly attached to the membrane by a core set of proteins (a process termed vesicle docking and priming). Upon arrival of an action potential and subsequent opening of presynaptic voltage-gated Ca2+channels (VGCCs), elevated Ca2+ triggers some of these prepared SVs to fuse with the plasma membrane within a fraction of a millisecond, rapidly transmitting a chemical signal across the cleft
This all happens in a fraction of a millisecond. Let that sink in.
A local reserve of SVs replenishes the “release-ready” vesicles on a subsecond time scale to sustain ongoing synaptic activity. Just after fusion, the bolus of neurotransmitter rapidly dissipates within the cleft via diffusion, binding to transporters, and in some synapses, by enzymatic degradation.
The neurotransmitters only have a brief window of time to bind to one of the receptors on the receiving neuron, usually AMPA receptors. The signals are received by a protein-dense region called the post-synaptic density (PSD).
Held et al. wanted to know if the neurotransmitters follow a direct path from AZ to receptor, in what has been dubbed a “nanocolumn” (NC). The surprising answer was: some do, but others do not. A membrane-proximal synaptic vesicle (MPSV) usually travels straight to an AMPA receptor but might travel obliquely to a different one, or to a different receptor like NMDA. This mechanism possibly allows additional information to be conveyed to the receiving neuron.
Whether AMPA receptors were corralled within PSD nanoclusters or randomly distributed across the postsynaptic membrane, the average response to the fusion of a MPSV (mean number of open AMPA receptors) was similar. By contrast, variability between each distinct MPSV simulation was increased when AMPA receptors were clustered instead of uniformly distributed. One implication of this simulation is that, assuming AMPA receptors adopt a clustered arrangement within the PSD, then some SVs have a larger postsynaptic impact than others. Given previous observations that NCs at these synapses may be altered by synaptic plasticity, perhaps the lack of correlation between MPSVs and PSD nanoclusters observed in this study provides a substrate for boosting synaptic strength via tightening the alignment between MPSVs and PSD receptor clusters. Combined with previous proposals for enhanced AMPA receptor clustering in response to plasticity induction, these effects could harness the variability observed on the simulations of Held et al to produce a large enhancement in synaptic strength.
For those interested in getting into the weeds, the paper and commentary give the names of numerous proteins involved in this rapid transfer of information across the synapse. The authors conclude with a statement of fine tuning:
Together, our data support a model in which synaptic strength is tuned at the level of single vesicles by the spatial relationship between scaffolding nanoclusters and single synaptic vesicle fusion sites.
As impressed as Dittman was by the work, he realizes it leaves many questions:
How are the AZ protein complexes arranged to couple Ca2+ elevation to exocytosis on such a rapid time scale? And related to this, are there special sites in the AZ where SVs dock, prime, and fuse or can SVs fuse anywhere on the AZ membrane? Are SV fusion sites precisely aligned with postsynaptic receptor clusters to ensure maximal receptor activation? Are there different types of synaptic transmission events that convey distinct information between the synaptic partners?
That last question opens the possibility of reasons for the kludge of synaptic transmission: “distinct information” can be transmitted depending on the neurotransmitter, its path, its timing, and its receptor. Indeed, a team of researchers in China and Singapore has been inspired to mimic the synapse in smart wearable materials to allow for more efficient and variable information flow via multiplexing — i.e., conveying multiple types of information over the same communication channel. Why? Because “Information in biological entities is conveyed by solvated ion carriers in water environments, allowing integration, parallelism, and optimal power consumption to control motion,” they said in their paper that was published in PNAS.
Pruning and Self-Tuning
Functioning neural circuits rely on the precise wiring of neurons to their appropriate synaptic partners. Initially, these connections are imprecise, with neurons making contacts with multiple different potential partners. These connections become more precise through a process called synaptic pruning, which eliminates unnecessary synapses.
To me, it’s not enough to quote Hebb’s Law that “New branches tend to be added at the loci where spontaneous activity of individual branches is more correlated with retinal waves, whereas asynchronous activity is associated with branch elimination.” Something else is controlling the synchronization of activity, else the pruning would leave only the strongest branch. A rose gardener knows when the pruning has been optimized for flowering. Something is telling a nerve network when optimality has been reached.
Another paper in PNAS offered additional reasons for synapses instead of direct junctions. Xiong et al. wrote about self-tuning of presynaptic neurons, even in lowly roundworms:
Faced with a myriad of internal and external challenges, neurons display remarkable adaptability, adjusting dynamically to maintain synaptic stability and ensure the fidelity of neural circuit function. This homeostatic adaptability is essential not only for neural circuit integrity but also has implications for various psychiatric and neurological pathologies. At the presynaptic terminal, the influx of calcium through specific ion channels is necessary for the exocytosis of neurotransmitter-filled synaptic vesicles. Our studies in the nematode Caenorhabditis elegans reveal a sophisticated mechanism where the abundance of presynaptic calcium channels is negatively regulated by the efficiency of synaptic vesicle exocytosis. This self-regulating mechanism ensures that presynaptic neurotransmitter release is autonomously adjusted, thereby maintaining synaptic function and safeguarding the robustness of neural communication.
Now I’m starting to get it. The reason for the kludgy synapse design is greater flexibility, information flow, and adaptability. And if the transmission still occurs within milliseconds, who is going to complain about the result? I can still jump onto that rock without falling. Life is good.
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