Cellular/Molecular
Neurons Expressing TRPV1 or M8 Sense Wide Range of Temperatures
Leah A. Pogorzala, Santosh K. Mishra, and Mark A. Hoon
(see pages 5533–5541)
Thermosensation is mediated by somatosensory neurons that express transient receptor potential (TRP) channels, notably TRPV1, which is activated by noxious heat, and TRPM8, which is activated by cool temperatures. Activation of either channel is thought to be modulated by other thermally responsive proteins, including TRPA1 and Mrgprd, but how these and other receptors interact to enable mammals to discriminate temperatures is unclear. Pogorzala et al. compared mice lacking TRPV1 or TRPM8 channels to mice in which neurons expressing these channels were selectively killed. Interestingly, killing the neurons altered mice's temperature preferences more than simply deleting the channels. TRPV1-null mice showed normal aversion to temperatures above 40°C, whereas those lacking TRPV1-expressing neurons tolerated temperatures up to 50°C. Similarly, mice lacking TRPM8-expressing neurons exhibited less cold aversion than TRPM8-null mice. Ablating TRPV1- or TRPM8-expressing neurons also raised or lowered mice's preferred ambient temperature, respectively. And deleting Mrgprd-expressing neurons along with TRPV1- or TRPM8-expressing neurons further reduced sensitivity to temperature extremes.
Development/Plasticity/Repair
Locally Synthesized β-Catenin Modulates Synaptic Vesicle Release
Anne Marion Taylor, Jason Wu, Hwan-Ching Tai, and Erin Schuman
(see pages 5584–5589)
Although initially controversial, the hypothesis that proteins are synthesized locally from mRNAs transported into axons is now widely accepted. During development, local protein translation is required for axons to respond to cues that promote elongation, turning, branching, and synaptogenesis. Taylor et al. report that β-catenin is one of the proteins locally translated during synaptogenesis. β-Catenin is important in intracellular communication mediated by Wnt signaling and N-cadherin-dependent cell adhesion and, as such, appears to have important roles in synapse formation and plasticity. In rat hippocampal cultures, axonal contact with polylysine-coated beads induced formation of presynaptic boutons. β-Catenin mRNA accumulated along with ribosomal protein near contact sites. Local inhibition of protein synthesis or knockdown of β-catenin mRNA reduced β-catenin levels at contact sites, indicating that local translation is required for β-catenin accumulation in synaptic boutons. Local silencing of β-catenin mRNA also increased vesicle release at contact sites, suggesting that β-catenin helps limit synaptic vesicle release, consistent with its proposed role in regulating vesicle pools.
Systems/Circuits
Efferent Input Limits Hearing Loss from Moderate Noise
Stéphane F. Maison, Hajime Usubuchi, and M. Charles Liberman
(see pages 5542–5552)
Mammalian cochleas have inner and outer hair cells (IHCs and OHCs). Depolarized IHCs activate afferent terminals of the auditory nerve, which carry the auditory signal to the brain. Depolarization of OHCs, in contrast, causes the cells to contract longitudinally, which can amplify the vibration of the basilar membrane. This in turn increases stimulation of inner hair cells, thus enhancing auditory sensitivity. OHCs are sparsely innervated by auditory afferents, but they receive direct hyperpolarizing input via olivocochlear (OC) efferents from the medial (M) superior olive. This efferent input suppresses OHC-dependent amplification. The function of this suppression is debated, but one hypothesis is that it limits noise-induced hearing loss. In fact, this has been demonstrated for noise >100 dB. Maison et al. now show that it is also true for moderately loud noise (84 dB). A week of noise exposure caused loss of afferent synapses on mouse IHCs, but no permanent auditory threshold elevation. Removing MOC efferents, however, increased synapse loss and caused permanent threshold shifts.
Prolonged exposure to moderately loud noise reduces afferent innervation of IHCs (base marked by solid line, nucleus marked by dashed line), and causes presynaptic ribbons (red) to appear away from postsynaptic densities (green; orphan ribbons indicated by red arrows). See the article by Maison et al. for details.
Neurobiology of Disease
TRPV1 and TRPA1 Lead Transition to Chronic Pancreatitis
Erica S. Schwartz, Jun-Ho La, Nicole N. Scheff, Brian M. Davis, Kathryn M. Albers, et al.
(see pages 5603–5611)
The pancreas synthesizes digestive enzymes, stores them in an inactive state, and releases them into the small intestine. Injury or disease can cause activation of digestive enzymes within the pancreas, however, resulting in autodigestion of the gland and release of cytokines. Digestive enzymes and cytokines activate nociceptive fibers that innervate the pancreas, resulting in pain sensation. Activated nociceptors release neuropeptides not only in the spinal cord, but also in the pancreas, where they trigger vasodilation, edema, and neutrophil infiltration, i.e., neurogenic inflammation. The pancreas can recover from acute inflammation, but repeated bouts lead to permanent damage. Schwartz et al. present evidence that the transition from acute to chronic pancreatitis requires activation of TRPV1 and TRPA1 on nociceptive afferents. In mice, repeated pancreatic insult caused neurogenic inflammation, neutrophil infiltration, upregulation of TRPV1 and TRPA1, increased afferent innervation, and pancreatic atrophy starting after 3 weeks. These changes were prevented if mice were treated with TRPV1 and TRPA1 antagonists before, but not after this time point.
