Activity Induces Presynaptic CaMKII Clustering In Vivo
Dinara Shakiryanova, Takako Morimoto, Chaoming Zhou, Amit K. Chouhan, Stephan J. Sigrist, et al.
(see pages 9093–9100)
Ca2+/calmodulin-dependent protein kinase II (CaMKII) is present in postsynaptic terminals, where it is activated by calcium influx through NMDA receptors. Upon activation, CaMKII undergoes autophosphorylation, enabling it to remain active when Ca2+ levels subside, and it clusters at postsynaptic sites where it helps mediate long-term potentiation. CaMKII is also present presynaptically, where it is activated by calcium release from the endoplasmic reticulum (ER) and regulates excitability and neurotransmitter release. Potassium-induced depolarization causes clustering of CaMKII at presynaptic boutons, but whether this occurs under physiological conditions was questioned. Using a fluorescently tagged CaMKII that reports activation state, Shakiryanova et al. found that muscle contractions in intact Drosophila embryos induced CaMKII activation and clustering in motor axon terminals. Voltage-sensitive Ca2+channels, ER ryanodine receptors, and inositol trisphosphate receptors contributed to activity-induced activation of presynaptic CaMKII. Although CaMKII activation was typically accompanied by clustering near active zones, activation and clustering could be independently manipulated.
Hypoxia Increases Neurogenic Potential of CNS Stem Cells
Baoyuan Bi, Natalina Salmaso, Mila Komitova, Maria V. Simonini, John Silbereis, et al.
(see pages 9205–9221)
Radial glia generate astrocyte-like stem cells that express glial fibrillary acidic protein (GFAP) and persist into adulthood. Whereas GFAP-positive stem cells that reside in the mature subventricular zone produce olfactory bulb neurons as well as glia, those that reside in the cortical parenchyma primarily produce astrocytes. Early brain injury can stimulate the latter cells to produce neurons, however. Bi et al. subjected young mice to reduced oxygen levels and then used a fluorescent marker to identify the progeny of GFAP-expressing cortical stem cells. Initially, only neural precursor cells were labeled, but after 3 weeks, some labeled cells also expressed neuronal markers, and later, some resembled morphologically mature neurons. Cortical GFAP-expressing cells from mice raised under hypoxic conditions self-renewed in vitro and could be induced to differentiate into neurons, astrocytes, and oligodendrocytes. Moreover, whereas stem cells maintained at normal oxygen levels in vitro produced only glia, those maintained at reduced oxygen levels sometimes produced neurons.
Single Impulses Elicit Properly Timed Purkinje Cell Responses
Dan-Anders Jirenhed and Germund Hesslow
(see pages 9070–9074)
Trace eye blink conditioning, in which a tone precedes and temporally overlaps with a tactile stimulus to the eye, is mediated by cerebellar plasticity. Information about the conditioned stimulus (CS) reaches the cerebellum via mossy fibers, which synapse on granule cells, and is transmitted to Purkinje cells via parallel fibers. Information about the unconditioned stimulus (US) is transmitted to Purkinje cells via climbing fibers. After conditioning, Purkinje cells respond to the CS with a pause in tonic firing, which determines when the conditioned response (CR) occurs. The CR occurs at the predicted onset time of the US, suggesting that parallel fiber activity during US onset determines the timing of the Purkinje cell pause. But Jirenhed and Hesslow found that after an association was learned, single impulses in mossy fibers were sufficient to drive temporally appropriate Purkinje cell responses, suggesting that the timing of the CR is determined by the onset time of the CS, not that of the US.
Neurobiology of Disease
Brain Infusion of Cyclodextrin Reduces NPC1-Related Degeneration
Amal Aqul, Benny Liu, Charina M. Ramirez, Andrew A. Pieper, Sandi Jo Estill, et al.
(see pages 9404–9413)
Cholesterol is an essential component of membranes and its turnover is particularly high in neurons, where it is required for synaptic remodeling and constructing lipid rafts, which serve as signaling platforms. Neurons can synthesize cholesterol, but their rate of synthesis is thought to be insufficient to generate adequate supplies. Therefore, it is hypothesized that cholesterol synthesized by astrocytes is transported to neurons. Imported cholesterol must be freed from carrier proteins within endosomes, and mutations of proteins involved in endosomal processing cause cholesterol to accumulate in these compartments. Mutations in NPC1, a protein required to transport cholesterol out of endosomes, cause Niemann-Pick disease C, which is characterized by endosomal cholesterol sequestration and subsequent neurodegeneration. Aqul et al. show that long-term intraventricular infusion of cyclodextrin, a molecule that facilitates cholesterol export from endosomes, prevented cholesterol sequestration and neurodegeneration in NPC1-null mice, suggesting that similar therapies might ameliorate Niemann-Pick disease C.