A New Function for Endocannabinoids?
Rita Nyilas, Barna Dudok, Gabriella M. Urbán, Ken Mackie, Masahiko Watanabe, Benjamin F. Cravatt, Tamás F. Freund, and István Katona
(see pages 1058–1063)
Much accumulated evidence has suggested that endocannabinoids act as retrograde signaling molecules at synapses. But results presented by Nyilas et al. in this issue indicate that the prototypical endocannabinoid anandamide does not share this function. Using in situ hybridization and immunogold labeling, the authors examined the expression pattern of N-acylphosphatidylethanolamine-hydrolyzing phospholipase D (NAPE-PLD), an anandamide-synthesizing enzyme, in mouse brain. They found that NAPE-PLD is associated with smooth endoplasmic reticulum cisternae in presynaptic glutamatergic terminals in several brain regions, with especially high expression in the mossy fiber terminals of dentate granule cells. This differs from the expression of the synthesizing enzyme for 2-arachidonoylglycerol, another major endocannabinoid, which is postsynaptic and adjacent to presynaptic terminals that express the cannabinoid receptor CB1. Intriguingly, CB1 is not expressed in the vicinity of mossy fiber terminals, suggesting that another endocannabinoid receptor is awaiting discovery.
A Longitudinal Study of Experimental Stroke
Ralph Weber, Pedro Ramos-Cabrer, Carlos Justicia, Dirk Wiedermann, Cordula Strecker, Christiane Sprenger, and Mathias Hoehn
(see pages 1022–1029)
Longitudinal studies of functional recovery from stroke in animals have been hindered by the inability to perform sequential studies in the same animal—mainly because the anesthetic that allowed functional magnetic resonance imaging (fMRI) based on blood oxygenation level-dependent (BOLD) contrast also caused severe side effects that precluded repetition. Weber et al. have developed a new anesthetic that overcomes this obstacle, and in this issue they describe a longitudinal fMRI study of recovery from focal ischemic brain injury in rats. They found wide interindividual variation in the damage caused by a defined injury, and moreover, functional loss was poorly correlated with lesion volume: some animals with large lesions had minimal functional loss, whereas some with minor lesions showed severe impairment. Nevertheless, they found strong correlation between BOLD signals and somatosensory evoked potentials, and between MRI and histological measures of lesion volume, indicating that MRI measurements accurately reflect functional and structural damage and recovery.
Vestibular Responses of Cerebellar Interneurons
Neal H. Barmack and Vadim Yakhnitsa
(see pages 1140–1152)
The output of the cerebellar cortex is encoded by simple and complex spiking of Purkinje cells. Complex spikes are triggered by climbing fiber inputs, but what determines the frequency of simple spikes is unclear. In attempting to answer this question, Barmack and Yakhnitsa have taken a bold step toward understanding cerebellar circuitry. Hypothesizing that cerebellar interneurons may modulate simple spiking, the authors recorded from each of six types of interneurons in mice. At the same time, they stimulated vestibular afferents—one of the main inputs to the cerebellum—by tilting the mouse using a vestibular rate table. They examined the spike trains of each neuron to determine whether its spike rate was modulated by the vestibular input and whether firing increased during ipsilateral or contralateral roll tilt. By comparing the phase of firing to that of Purkinje cells, they determined that stellate and basket cells could influence the timing of simple spikes.
Neurobiology of Disease
Context-Specific Mechanotransduction by TRPV4
Nicole Alessandri-Haber, Olayinka A. Dina, Elizabeth K. Joseph, David B. Reichling, and Jon D. Levine
(see pages 1046–1057)
An unusual feature of transient receptor potential vanilloid (TRPV) channels is their sensitivity to diverse stimuli, which enables them to integrate multimodal sensory information. For example, TRPV4 is sensitive to heat, osmolarity, pH, and several ligands, and it appears to be involved in sensory transduction during inflammation. This week, Alessandri-Haber et al. elaborate the role of TRPV4 channels in neuropathy. Diverse treatments and conditions—including chemotherapy agents, AIDS drugs, diabetes, and/or alcoholism—increase animals' sensitivity to mechanical stimuli, resulting in hyperalgesia. Alessandri-Haber et al. showed that TRPV4 antisense oligonucleotides greatly reduced the mechanical hyperalgesia normally produced by these conditions, without altering normal pain thresholds. A similar reduction in hyperalgesia was produced by α2 integrin antisense oligonucleotides and inhibitors of Src tyrosine kinases. Furthermore, a Src tyrosine kinase activator induced mechanical hyperalgesia that was blocked by TRPV4 antisense oligonucleotides. The results suggest that TRPV4 interacts with α2 integrin and Src tyrosine kinases to mediate context-specific mechanotransduction.