Cellular/Molecular
Uncaging Endocannabinoids
Thomas Heinbockel, Darrin H. Brager, Christian G. Reich, Jun Zhao, Sukumaran Muralidharan, Bradley E. Alger, and Joseph P. Y. Kao
(see pages 9449-9459)
This week, Heinbockel et al. provide a novel (and legal) way to light up cannabis. Endocannabinoids (eCBs) are among a group of small lipid molecules that exert their modulatory effects through intercellular retrograde signaling. However, the complexity of their biosynthesis and delivery to effectors has made it difficult to examine the dynamics of their action. The authors examined this issue by photolytic release of a novel caged version of the eCB, anandamide. Using depolarization-induced suppression of inhibition as their bioassay, the authors report that intracellular signaling downstream of the CB1 receptor, rather than eCB biosynthesis or transmembrane diffusion, is rate limiting for eCB signaling. They estimated that eCBs were synthesized and released within 75-190 ms, much more quickly than originally thought. Given that their experiments were performed at room temperature, one expects even faster signaling in vivo, on par with other G-protein-coupled responses.
Development/Plasticity/Repair
ChAT-Free Retinal Waves
Rebecca C. Stacy, Jay Demas, Robert W. Burgess, Joshua R. Sanes, and Rachel O. L. Wong
(see pages 9347-9357)
Early and local spontaneous activity is increasingly recognized as important in the development of neural circuits. Waves of activity in the retina precede sensory stimulation, being coordinated first by gap junctions. Later, retinal waves depend on cholinergic and then glutamate synaptic activity. This week, Stacy et al. focus on the cholinergic component. The authors conditionally deleted the acetylcholine-synthesizing enzyme choline acetyltransferase (ChAT) under control of the retinal-specific element of the Pax6 promoter. ChAT was absent from the retina with the exception of a small wedge-shaped wild-type (WT) region. Consistent with previous reports of cholinergic dependence of early wave generation, waves were restricted to the WT region during the first few postnatal days. However, by postnatal day 5 ChAT-deficient regions could propagate and initiate waves, although with different spatiotemporal characteristics than WT mice. The makeshift waves were not driven by chemical transmission but instead required gap junctional networks. You can't keep a good wave down it seems.
Genetic ablation of cholinergic transmission from starburst amacrine cells in the mouse retina. Red regions show immunolabeling for ChAT, and green regions (green fluorescent protein) mark locations where ChAT expression is absent. See the article by Stacy et al. for details.
Behavioral/Systems/Cognitive
Mirror Neurons and Motor Memory
Katja Stefan, Leonardo G. Cohen, Julie Duque, Riccardo Mazzocchio, Pablo Celnik, Lumy Sawaki, Leslie Ungerleider, and Joseph Classen
(see pages 9339-9346)
Against the odds, our brains can learn not only by doing, but also by simply watching. So-called “mirror neurons” discharge when monkeys either execute an action or observe others performing the same action. In this week's Journal, Stefan et al. show that mirror neurons may participate in motor learning in humans. The authors showed previously that thumb movements evoked by transcranial magnetic stimulation (TMS) of the primary motor cortex shifted in direction after physical practice. Here, they examined the effects of just observing the movement in the form of a videotaped actor moving his thumb in a prescribed direction. Human subjects who watched the videotape made more TMS-evoked movements that fell within the training target zone (TTZ), which was oriented opposite to that of their previously determined habitual movement. Watching or practicing the movement produced similar results, suggesting that activation of the mirror neuron system generates a lasting memory trace that can contribute to motor learning.
Neurobiology of Disease
Gene Transfer in a Lysosomal Storage Disease
Gumei Liu, Inês Martins, John A. Wemmie, John A. Chiorini, and Beverly L. Davidson
(see pages 9321-9327)
The enzyme defects that underlie lysosomal storage diseases (LSDs), although rare, can cause failure of multiple organs, including the CNS. Although enzyme replacement has improved the systemic manifestations of several LSDs, including Gaucher's disease and Fabry's disease, treatment of the CNS manifestations remains a challenge. This week, Liu et al. used adeno-associated virus type 4 (AAV4) vectors to target mutant mice deficient in β-glucuronidase, an animal model of mucopolysaccharidosis type VII (MPS VII). The authors injected AAV4 vectors encoding β-glucuronidase into the ventricles. Ependymal cells expressed the enzyme and secreted it into the CSF. Four weeks after treatment, glucuronidase had penetrated throughout the brain. Immunoreactivity for the substrates chondroitin sulfate and heparan sulfate declined, as did lysosomal distention, presumably because affected cells endocytosed the soluble enzyme. Treatment also improved progressive behavioral deficits seen in MPS VII mice, as measured by context fear conditioning.
