Karl is taking over!

Karl Deisseroth and co-workers have two papers online that develop and apply the channelrhodopsin technology for which he has become so famous. In Nature they develop two new light controlled genetic probes to upregulate adenylate cyclase or phospholapise C. The former gives more cAMP, the latter more IP3. They insert these probes into the Nucleus accumbens and use light to modulate neuronal firing rates. Finally, they used their probes to control the behaviour of mice.

In Science they show work using ChR2 to analyze circuits in a mouse model of Parkinson's disease. This is a harder paper to follow (frankly), as it assumes knowledge of this area I do not have. I get the impression that their findings were a surprise. They make a bunch of new mice with ChR2 (or variants) in different areas of the brain, and none of these have any really effect on their model. Then, they turn (ironically?) to a Feng mouse (JAX stock number: 007615, strain: B6.Cg-Tg(Thy1-COP4/EYFP)9Gfng/J) and find that high frequency stimulation of cortical neurons helps locomotion behaviour in their mouse model.

Does Jay Leno know about this work yet?

Temporally precise in vivo control of intracellular signalling. Nature 10.1038/nature07926.

Optical deconstruction of Parkinsonian neural circuitry. Science 10.1126/science.1167093.

CaMK-2 activation is synapse specific during LTP.

Ryohei Yasuda and co-workers paper combing 2-photon uncaging of MNI-glu and FRET-FLIP imaging of CaMK-2 is finally out in Nature this week (those who read Ryohei's Japanese weblog know this paper was accepted a while ago). I had briefly mentioned this technical tour-de-force recently in discussing Sabatini latest Neuron paper using the "PiSing technique" originally developed by Matsuzaki and Kasai. Yasuda's group showed some of their data at SfN in DC last November. Like Kasai, Sabatini and Svoboda, they report synapse-specific induction of LTP using 2P uncaging of MNI-glu induces large and permanent volume changes of targeted spine heads, whilst the near by spines are essentially unaffected. This is due to the exquisite resolution of 2PP (less than 2 microns). In this Nature article Yasuda's lab use FRET-FLIM imaging to reveal that the kinase is only active for a brief period, even though it effects are long lasting. Given Kasai's work, this does not seem too surprising to me. But what do I know?

Seok-Jin R. Lee, Yasmin Escobedo-Lozoya, Erzsebet M. Szatmari & Ryohei Yasuda.
Activation of CaMKII in single dendritic spines during long-term potentiation. Nature (2009) 458:299-304.

A small gripe: the supplemental movies do not play on an Apple computer! This is not unique, would it kill journals to check this before they publish them? About 25% of academics use a Macintosh.

Matsuzaki, M., Honkura, N., Ellis-Davies, G. C. & Kasai, H. Structural basis of long-term potentiation in single dendritic spines. Nature (2004) 429:761-6.

Calcium on the brain.

Brian Bacskai has a lovely paper on how Alzheimer's disease changes astrocytic calcium signaling. (Synchronous hyperactivity and intercellular calcium waves in astrocytes in Alzheimer mice. Science 27 February 2009, Vol. 323. no. 5918, pp. 1211 - 1215. DOI:10.1126/science.1169096)
They find that in a mouse model of AD that amyloid-beta plaques are foci for the initiation of calcium waves in the astrocyte network. Further, diseased mice have higher resting calcium than normal mice. They use a well established mouse model of AD (APPswe:PSdeltaE9, this has APP Swedish mutations Lys670Asn & Met671Leu, and PS1 Pro264Leu, and is available from Jackson Labs). The advantage of this model is that plaques occur early in life (4.5 months) so it makes research a bit cheaper to do (lower cage costs). It should be stressed that this model along with most other mouse models of AD do not show neuronal loss. Neuronal death from AD is, of course, the fundamental human problem. Karen Ashe has suggested that such mice are models only of the early stages of AD in humans. So she has recently developed a very cool new mouse model in which plauqes and tangles (hyperphosphorylated tau) are inducible (tet-off system). The Ashe mouse shows neuronal loss. As far as I know this is unique mouse model. Back to Bacskai. He finds that calcium transients in astrocytes occur more frequently in AD than WT mice. These signals are somewhat larger than normal and are synchronous. Finally they are not dependent upon neuronal activity. These results suggest that plaques change the calcium buffering of astrocytes in a significant way. (As a side-note, I talked with the first author, Kishore, at SfN in DC in 2008, who told me no one in his lab though looking at astrocytes was worth while. Not a bad result for such an unpromising start!) Similar results have been reported by Haydon and Nedergaard for epilepsy, linking calcium waves to another disease (note most glia biologists now think that in vitro calcium waves are artifactual). It will be interesting to see what the mechanistic explanation is for these transients, and if more advanced mouse models show similar trends.

Amyloid Plaque and Neurofibrillary Tangle Pathology in a Regulatable Mouse Model of Alzheimer’s Disease. Am. J. Path. (2008) 173:762-772.

Enhanced astrocytic Ca signals contribute to neuronal excitotoxicity after status epilepticus. J. Neurosci. (2007) 27:10674-10684.

An astrocytic basis of epilepsy. Nature Med. (2005) 11:973-981.

Animal models of Alzheimer's disease and frontotemporal dementia. Nature Rev. Neurosci. (2008) 9:532-544.