Targeting of 5-HT1A Receptors
Damien Carrel, Justine Masson, Sana Al Awabdh, Catherine Borg Capra, Zsolt Lenkei, Michel Hamon, Michel Boris Emerit, and Michèle Darmon
(see pages 8063–8073)
Depression is associated with decreased binding of serotonin 5-HT1A receptors. Receptors must be targeted to the appropriate membrane domain to function properly, and although trafficking mechanisms have been elucidated for some receptors, little is known about how serotonin receptors are targeted to dendrites. Because the C terminus of 5-HT1A receptors is required for targeting, Carrel et al. screened for proteins that directly interact with this domain in rat hippocampus. They identified Yif1B, a homolog of a yeast protein involved in transport between the endoplasmic reticulum (ER) and Golgi apparatus. Yif1B colocalized with 5-HT1A receptors in vesicle-like puncta in the soma and proximal dendrites of hippocampal neurons, and colocalized with ER markers in transfected cell lines. The authors report that knockdown of Yif1B by RNA inhibition in cultured neurons prevented expression of 5-HT1A receptors in distal dendrites, but did not alter the expression pattern of other receptors, suggesting a specific role in targeting 5-HT1A receptors.
Seizure-Induced AMPA Receptor Phosphorylation
Sanjay N. Rakhade, Chengwen Zhou, Paven K. Aujla, Rachel Fishman, Nikolaus J. Sucher, and Frances E. Jensen
(see pages 7979–7990)
Seizures in neonates are usually caused by hypoxia and can increase risk of later epilepsy and cognitive impairment. Rakhade et al. induced hypoxic seizures in early postnatal rats to identify molecular changes that increase seizure susceptibility. Seizures increased the amplitude and frequency of miniature and spontaneous EPSCs mediated by AMPA receptors (AMPARs) within 1 h. This increase likely resulted from increased phosphorylation of AMPAR subunits by PKA, PKC, and calcium/calmodulin-dependent kinase II, because the activity of these kinases was elevated. Phosphorylation of GluR1 was increased at sites that increase channel conductance and synaptic insertion, whereas GluR2 was phosphorylated at a site that leads to its internalization. GluR2 internalization can increase the number of calcium-permeant AMPA receptors, which could further increase excitability. In vivo treatment with AMPAR antagonists blocked increases in phosphorylation, EPSC amplitude, and EPSC frequency, and also attenuated susceptibility to later seizures.
Lateralization of Speech Comprehension
Jonas Obleser, Frank Eisner, and Sonja A. Kotz
(see pages 8116–8123)
Speech comprehension involves both brain hemispheres, but the extent to which the hemispheres have overlapping functions is not clear. One hypothesis suggests that the hemispheres differ in their processing of temporal and spectral information. To test this, Obleser et al. presented spoken words to human subjects while measuring cortical activity using functional magnetic resonance imaging. Using noise vocoding, a technique that permits independent manipulation of frequency and spectral information, voice recordings were degraded in five steps in each dimension, resulting in 25 conditions. Comprehensibility declined with degradation in each dimension, and cortical activation correlated with comprehensibility. All conditions activated the anterior superior temporal cortex bilaterally, but the peak and extent of activation in the two hemispheres varied: the right hemisphere was more sensitive than the left to spectral variation, whereas the left hemisphere was more sensitive to temporal variation. The results indicate mild lateralization of these elements of speech processing.
Neurobiology of Disease
Pain Mediation by Innocuous Sensory Afferents
Simona Neumann, Joao M. Braz, Kate Skinner, Ida J. Llewellyn-Smith, and Allan I. Basbaum
(see pages 7936–7944)
Expression of protein kinase C γ (PKCγ) in interneurons of lamina II of the spinal cord dorsal horn is thought to be essential for mechanical allodynia, a painful response to normally innocuous stimuli. Nonpeptidergic nociceptors were initially assumed to innervate PKCγ interneurons, because they terminate in the same sublamina. Neumann et al. now show that the terminals of nonpeptidergic nociceptor afferents terminate dorsal to the PKCγ interneurons, with only minimal overlap. In contrast, the terminals of medium- and large-diameter myelinated afferents overlapped extensively with PKCγ neurons, and electron microscopy showed direct synapses between terminals of large-diameter, myelinated afferents and PKCγ interneurons. Moreover, innocuous stimulation (walking on a rotarod) increased Fos expression in PKCγ interneurons, whereas painful stimuli did not. Therefore, a normally innocuous pathway appears to mediate allodynic pain. But the modality of sensory information carried by the afferents that innervate the PKCγ interneurons remains unknown.