Cellular/Molecular
Navβ1 Regulates Expression of A-Type K+ Channels
Céline Marionneau, Yarimar Carrasquillo, Aaron J. Norris, R. Reid Townsend, Lori L. Isom, et al.
(see pages 5716–5727)
Most ligand- or voltage-gated ion channels have accessory subunits that regulate channel expression, trafficking, and/or stabilization. Several accessory subunits that associate with voltage-gated K+ channels have been identified. To discover additional subunits, Marionneau et al. used mass spectrometry to identify proteins coimmunoprecipitated from mouse brain with Kv4.2, the pore-forming subunit of A-type K+ channels. Surprisingly, one of these proteins was Navβ1, which was previously identified as a regulator of voltage-gated Na+ channels (NaV). Knocking down Navβ1 in cultured cortical neurons reduced IA current density without affecting kinetics or voltage dependence. Knocking out Navβ1 replicated effects of inactivating IA—increasing both action potential decay time and the number of action potentials elicited by prolonged current pulses—in cortical pyramidal neurons. This effect might explain why mutations in Navβ1 are linked to epilepsy. Interestingly, Navβ1 knock-out did not alter action potential threshold or peak amplitude, suggesting Navβ1 does not regulate NaV currents in cortical pyramidal neurons.
Repetitive firing induced by prolonged depolarization is greater in neurons lacking Navβ1 (right) than in wild-type neurons (left). See the article by Marionneau et al. for details.
Development/Plasticity/Repair
LIM Proteins Direct Brainstem Axon Trajectories
Ayelet Kohl, Yoav Hadas, Avihu Klar, and Dalit Sela-Donenfeld
(see pages 5757–5771)
Brainstem reticular nuclei contain mixed populations of neurons that project to different targets. Tracing the projections of specific classes of these neurons requires expression of fluorescent proteins under the control of subtype-specific enhancers. In developing chicks, this is achieved by electroporating fluorescent protein-expressing vectors, which allows unilateral labeling, thus facilitating discrimination of ipsilateral and contralateral projections. Although vector-mediated expression is transient, thus limiting how long axon growth can be watched, cotransfecting PiggyBac transposase, which excises the target gene from its vector and inserts it into the host genome, stabilizes expression. Using this method, Kohl et al. followed the development of chick dA1 interneuron progenitors, which give rise to brainstem cochlear and precerebellar nuclei. They discovered that the axons extended farther than previously thought, forming synapses in midbrain and Purkinje cell layers. Furthermore, the path followed by these axons was dramatically altered by replacing a dA1-specific LIM homeodomain transcription factor with one normally expressed in dB1 interneurons.
Behavioral/Systems/Cognitive
SCN Electrophysiological Rhythms Weaken with Age
Sahar Farajnia, Stephan Michel, Tom Deboer, Henk Tjebbe vanderLeest, Thijs Houben, et al.
(see pages 5891–5899)
Neurons in the suprachiasmatic nucleus (SCN) coordinate circadian rhythms in various physiological functions and behaviors. Besides exhibiting daily oscillations in gene expression, these neurons show circadian variation in spontaneous spiking, with higher firing rates occurring during the day in both nocturnal and diurnal animals. These rhythms depend on circadian variation in the magnitude of intrinsic ionic conductances, including K+ leak currents, which hyperpolarize the resting membrane potential (Vm) and are active at night; A-type K+ currents (IA), which regulate neuronal excitability and peak during the day; and fast delayed rectifier (FDR) K+ currents, which also peak during the day and underlie sustained firing. Farajnia et al. found no significant circadian variation in IA, FDR, Vm, or spontaneous firing rate in acute SCN slices from old mice. The loss of these oscillations likely contributes to the loss of normal sleep–wake cycles and the dampening of other circadian rhythms, which commonly occur with age.
Neurobiology of Disease
Extinction Deficits May Underlie Chronic Pain
Amelia A. Mutso, Daniel Radzicki, Marwan N. Baliki, Lejian Huang, Ghazal Banisadr, et al.
(see pages 5747–5756)
Acute pain activates several CNS regions, including somatosensory cortex (involved in pain localization and perception of intensity), prefrontal cortical areas (involved in pain evaluation), and anterior cingulate and insular cortices (involved in emotional responses to pain). The transition from acute pain to chronic pain, which persists long after an injury has healed, is thought to involve increased excitability and decreased gray matter volume in those brain areas, as well as recruitment of additional areas. Mutso and colleagues have proposed that chronic pain also stems partly from an inability to extinguish pain memories. In support of this hypothesis, they show that mice subjected to nerve injury had deficits in hippocampal-dependent fear extinction. Furthermore, hippocampal processes involved in fear extinction—including short-term plasticity, ERK signaling, and neurogenesis—were impaired in injured mice. Finally, human chronic pain patients had reduced hippocampal volume, which has also been linked to deficits in fear extinction.