What is your dirty little secret?

Let's be honest, no "novel" technology is perfect, unless your name is Gutenburg. And last time I looked it wasn't. So if you, like me, make technology for a living, I want you to confess, as Dwight Bergles would say: "What's your dirty little secret?" I was looking at the special issue of Brain Cell Biology on optical techniques and saw, much to my surprise, that optogenetics is not perfect after all.

Many of you will know that there has been a very Big Splash made with these light-controlled ion channels/pumps (see entry for 1st may 2007). What we now get to find out is that one half of yin-yang partnership ain't so great after all. It turns out most of the chloride pump (NpHR) never gets to the membrane in vivo, but gets caught up in the ER (see pic above, Fig. 3A from BCB (2008) 36:129-139). On the left, you see what happens to NpHR in a mouse, most of the protein gets stuck in the ER, often as huge blebs. With much tweeking, Deissseroth and co-workers have removed the blebbing, and improved the current/photon by up to 80%. Still relatively little protein ends up in the dendritic plasma membrane (right panels, eNpHR).

So, come on, confess, what's your dirty little secret?

"Plasticity Inducing Stimulus."

Sabatini and co-workers have a nice paper in this week's Neuron (11 December 2008). They use 2-photon uncaging of glutamate to induce spine head enlargement. This technique was of course invented by Haruo Kasai and Masanori Matsuzaki in 2004. It has also been used by Karel Svoboda and co-workers to great effect. Interestingly all 3 labs see more or less the same structural changes at targeted spine heads (see figure). Small spines undergo rapid enlargement (200-300% increase in volume), however only part of this increase in maintained for hours. Two other labs have also used Kasai's method to induce LTP at visually identified spine heads. Yasuda (Duke) and Hayashi (MIT) have both had abstracts at the past SfN annual meetings doing similar experiments to Sabatini's lab. They are all trying to parse out the details of the signaling processes involved in the initiation and maintenance of LTP used GFP-labeled proteins. Lots of interesting details are starting to emerge from these studies. Sabatini coins a new term for the Kasai/Matsuzaki LTP protocol: "Plasticity Inducing Stimulus" or "PS" for short. It is a pity he didn't add an extra I and S to this, that would have been very amusing.

Structural basis of long-term potentiation in single dendritic spines. Nature (2004) 429:761-6.

Locally dynamic synaptic learning rules in pyramidal neuron dendrites. Nature (2007) 450:1195-200.

Destabilization of the Postsynaptic Density by PSD-95 Serine 73 Phosphorylation Inhibits Spine Growth and Synaptic Plasticity. Neuron (2008) 60:788-802