Saturday, July 29, 2006

Gonna make you fall in love with...Spines   posted by Coffee Mug @ 7/29/2006 01:18:00 PM

Never ever let a n* ride if you think he's gonna slide pop'em in the' the money. - Bone Thugs N Harmony

The Genius is dead. Genius Re-post:

Your standard neuron in the cortex is called a pyramidal neuron. It generally has on big apical dendrite sticking out the top and a few basilar dendrites radiating around the bottom. Here's a glowing one:

This one comes from a somewhat troublesome paper from the lab of Karel Svoboda who as far as I can tell is a guru of new imaging techniques who happens to have an interest in the details of dendrites as well. The reason why the paper was a little vexing is because the results seemed to run against a large literature showing that the major identifiable morphological problem with neurons in Fragile X Syndrome brains has to do with dendritic spines. Let me back up. Your standard neuron in the cortex has dendrites and an axon. The axon is the output structure that goes and pokes at another neuron and can fire action potentials that release neurotransmitters from its tip to send signals. The dendrites are the parts that receive signals from axons. Where an axon and a dendrite meet is called a synapse. Dendrites are studded with these little knobby-doos called spines. Spines are where most excitatory synapses in the cortex are made.

Spines go through a maturation process whereby they initially come out as long wormy things called filopodia and then kind of settle back into a variety of shapes often resembling the power-up mushrooms in Super Mario Bros. or like a large kind of extended comma. The fat part at the end is referred to as the spine head and the thin part connecting to the dendritic shaft is the spine shaft.

Spine shapes change in the lifespan of the spine, but also change over the lifespan of the organism. And along side the changes in shape come changes in the number of spines per dendrite (the spine density). Since people had looked at adult human Fragile X brains and seen abnormalities with regard to spine morphology and density it seemed clear that something must be occurring during development.

Nimchinsky et al (2001) wanted to see what happens in development so they got some normal mice and some mice lacking fragile X mental retardation protein (FMRP) that are a pretty good model for what's happening in humans with the disorder. When the mice were one, two, or four weeks old they injected a particular part of the cortex with a fancy shmancy virus that lights up a good portion of neurons (anyone who reads science crap knows about GFP the magical jellyfish protein, that's how they're doing this). This allowed them to use laser microscopy to do detailed quantitative analysis on the spine lengths and density. The troublesome bit is that while they found the expected differences between FraX mice (the fragile X model) and wild-type (read: normal) mice at one week (shown below), the differences disappeared by 4 weeks. How can this be?!

They offered up a number of considerations including that they were looking at a different chunk of cortex than other people usually do and that perhaps there were some limitations to their visualization technique. The most important limitation, as it turns out, is that they can't use their technique past about 6 weeks of age because the virus they used is too bad at infecting neurons after that. A more recent paper from the Greenough group in Illinois, who were some of the major reporters of these fragile X spine abnormalities in the first place, arrived at a resolution to this conflict.

Galvez and Greenough (2005) took basically the same tack as the Svoboda group except they chose a couple of different ages. They used 25-day old mice to map onto the 4-week time point previously reported and they took another sample at age 73-76 days old. For those of you who have trouble dividing by 7, that's about 10-11 weeks. The reason for doing this is that it is understood that a major developmental process called pruning might be at play here. Initially developing brains produce huge amounts of connections during a period of widespread synaptogenesis. They don't need all of these connections. So they have to be 'pruned' back. There are lots of tree metaphors when talking about dendrites that can make it very pleasant for a neuroscientist to contemplate a tree in the park on a summer afternoon. This apparently happens in mice some time after one month of age.

The Greenough paper used a more rudimentary staining procedure so they could look at spines in the older brains. They managed to replicate for the most part the finding that FraX mice and wild-type mice don't differ at 4 weeks with regard to spine shape and density. But at the much later time point they differ pretty radically as illustrated here:

It appears that the major malfunction with Fragile X spines then isn't that they can't grow out right or anything like that. Its that they can't be eliminated after the fact. Notice how much more bare the adult wild-type dendrite (Figure 1C from the paper) looks compared to the FraX dendrite (Fig 1D). This is awfully nice to see for two reasons. One, because it clears up an apparent discrepancy in the literature and it turns out that everyone was right which ought to make all the labs involved feel marvelous. It's also nice because it indicates that the real neurological problems in Fragile X development start later than expected in development. I'm not quite clear on when this massive pruning event is supposed to happen in human development, but it opens a window whereby if we ever get the means to replace this protein we might ameliorate some of the effects of the syndrome.


Nimchinsky EA, Oberlander AM, Svoboda K (2001). Abnormal development of dendritic spines in FMR1 knock-out mice. J. Neurosci. 21:5139-5146.

Galvez R, Greenough WT (2005). Sequence of abnormal dendritic spine development in primary somatosensory cortex of a mouse model of the fragile X mental retardation syndrome. Am. J. Med. Genet. 135A:155-160.