End of year rant.

I started this weblog at the beginning of this year because I got so pissed off at the wretched News & Views in Nature Methods that WH Li wrote about our NDBF-EGTA paper. It seems fitting to end with another rant.

So what does it take to be news-worthy? In Science (doi:10.1126/science.314.5806.1674 , 15 December 2006) these is a three page article by the science journalist Greg Miller on “optogenetic” control of neuronal firing that features the work of three groups prominently. It starts with an account of a Jay Leno joke on Gero Miesenbock’s latest cool piece of science that was published last year (April 2005) in Cell (Yes, JAY LENO).

The next highlight is the collaborative work of the Isacoff-Trauner-Kramer Berkeley triumvirate. This group of talents has been working on cross-linking azobenzene probes to channel proteins for a few years. Dual wavelength irradiation opens and closes the channel. Very clever. This work has had a decent amount of scientific press (but nothing so cool as a Jay Leno joke).

The third highlight (we are told) comes from Stanford. This is where the account goes off the rails in my opinion. The journalist tells us that “Karl Deisseroth and colleagues” who are “across the San Francisco Bay” from the Berkeley group, have developed the third important new approach to optogenetic control of neuronal firing (using channelrhodopsin-2, ChR2: DOI 10.1038/nn1525). This one requires no exogenous ligand, like the other two, so is potentially much better.

What is so inaccurate about this account is the folk who actually pioneered ChR-2 are not even mentioned. Now this is a 3-page article, so don’t tell there is a lack of space, as much unpublished work is also mentioned. In fact, Deisseroth collaborated with the discovers of channelrhodopsin (Nagel & Bamberg in Frankfurt) on this work. Furthermore, the latter have used the same channel to control C. elegans movement (A&B in pic above, doi:10.1016/j.cub.2005.11.032, submitted 2 days after the Deisseroth paper appeared online). A Japanese group have also done similar work (Right panel in pic above, doi:10.1016/j.neures.2005.10.009).

So I have two questions (OK, gripes). Why can’t non-American groups get more credit for their work here in the USA? I actually know Nagel & Bamberg (I have spent 5-6 weeks in Bamberg’s lab over the years). I recall Bamberg saying this was always a problem, but I always told him he was being too sensitive. Japanese friends say the same thing, but I say that I am sure they have the wrong impression. This recent hype tends to make me agree with them.

Secondly, who do you have to know, and how much money do you have to pay for a 3-page highlight of your work in one of the two most widely read journals in the world?!

A glutamate receptor photo-switch.

Two labs at UC Berkeley (Isacoff & Trauner) have just published a "reversibly caged glutamate" in the Journal of the American Chemical Society (DOI: 10.1021/ja067269o)! They use information gleaned from the pharmacology literature (J. Med. Chem. 2000, 43, 1958-1968) to make a glutamate derivative that changes its affinity for certain types of excitatory glutamate receptors. Using 380 nm light they depolarise neurons, but with 500 nm light they reverse this reaction.

The idea is not new, Harry Wasserman did similar things in the 1970s with "bis-Q", that was later exploited by a young Henry Lester. The problem with bis-Q was that its inactive form was an antagonist, so this prevented useful experiments.

Isacoff & Trauner have revived this cool idea in a very elegant paper. It will be intteresting to see if it goes beyond the gee-wiz to give real biology.

Two-photon uncaging comes of age?

In November & December 2006 two more groups reported 2P uncaging of MNI-glutamate. This makes 6 who have reported such. The work of Magee, Sabatini and Svoboda have been mentioned here already. Now Yuste (doi:10.1073/pnas.0609225103 & doi:10.1073/pnas.0608755103 ) and Huganir (doi:10.1073/pnas.0608492103 ) have used the approach originally published by us with Kasai in Nature Neuroscience in 2001.

Huganir shows lovely AMPA-R currents from CA1 that mimic a mEPSC recorded in the same preparation (B above). We called these 2pEPSC in 2001. Kasai reminded me recently that he and I discussed at length what to call these. I suggested "uEPSC"-wanting one simple lower case letter to replace the "m" of the mini in mEPSC. But Kasai wisely said this did not emphasize the distinctiveness of the technique, so he came up with "2pEPSC". Huganir uses "2P-EPSC", Svoboda "uEPSC", Sabatini "2PLU", Magee "gluEPSC"! [I would now say that "uEPSC" ought to be reserved for unitary-EPSCs.]

There are some slight differences reported in these papers to those previously: Huganir's lateral resolution (C, above) is somewhat worse than Magee's (e, left x-resolution, right z-resolution). Yuste reports that they see no correlation between spine head volume and AMPA-R density (probably due to resolution issues), but Haganir (not shown here) and Magee do (f above).

In spite of these quibbles, with the publication of 3 more elegant papers using MNI-Glu by two groups, I think we can say that 2-photon uncaging has come of age.