Cellular/Molecular
Effects of Kv7.2/7.3 Channel Are Location Dependent
Arne Battefeld, Baouyen T. Tran, Jason Gavrilis, Edward C. Cooper, and Maarten H. P. Kole
(see pages 3719–3732)
Ion channels' effects are influenced by surrounding proteins, such as accessory subunits and other ion channels. Therefore, the same channel can have different roles in different cells or in different parts of the same cell. Kv7.2/7.3 voltage-gated potassium channels, for example, have been found to both prevent axon potential initiation and increase spike amplitude. Although some evidence suggests that perisomatic and axonal Kv7.2/7.3 channels can have different properties, Battefeld et al. propose that the channel's role in rat cortical neurons is determined by its subcellular location. Kv7.2/7.3 channels in axon initial segments (AISs) and nodes of Ranvier had similar biophysical properties. But because AIS Kv7.2/7.3 channels were strongly activated during action potentials, they reduced the spike after depolarization, thus limiting repetitive spiking. Because spikes were narrower at nodes, however, they did not increase activation of nodal Kv7.2/7.3 channels. Nonetheless, nodal Kv7.2/7.3 channels hyperpolarized resting membrane potential, thus reducing steady-state inactivation of voltage-gated sodium channels. Consequently, more sodium channels opened during spikes, increasing spike amplitude.
Rat neocortical layer 5 neuron (red) processed with a paint daub filter. Kv7.3 channels (blue) colocalize with voltage-gated sodium channels (green) at the AIS and nodes of Ranvier. See Battefeld et al. for details.
Development/Plasticity/Repair
Nerve Injury Alters Distribution of Motoneuron Inputs
Travis M. Rotterman, Paul Nardelli, Timothy C. Cope, and Francisco J. Alvarez
(see pages 3475–3492)
Stretching a muscle activates IA afferents that innervate muscle spindles. The afferents activate motoneurons innervating the same muscle, causing contraction. This stretch reflex helps maintain balance and compensate for unexpected loads. Although peripheral axons regenerate after injury, the stretch reflex is permanently lost: IA afferents are activated by stretch, and electrical stimulation of the afferents evokes EPSPs in motoneurons, but muscle stretch does not modulate motoneuron firing. Rotterman et al. attribute this failure to changes in the distribution of afferent synapses on motoneuron dendrites. In uninjured rats, synapses from IA afferents were more numerous and clustered on proximal dendrites of motoneurons than on distal dendrites. After nerve transection and regeneration, synaptic density and clustering was greatly reduced, particularly on proximal dendrites, resulting in a more uniform distribution across the dendritic arbor. This redistribution might impair synaptic integration and/or prevent activation of active conductances in dendrites, thus preventing synaptic input from depolarizing the neuron to spike threshold.
Systems/Circuits
Noradrenergic Signaling Causes Cocaine's Aversive Effects
Jennifer M. Wenzel, Samuel W. Cotten, Hiram M. Dominguez, Jennifer E. Lane, Kerisa Shelton, et al.
(see pages 3467–3474)
Cocaine rapidly produces euphoria, but the euphoria is short-lived and often followed by anxiety, paranoia, or panic. These opposing effects cause rats to exhibit conflicting responses to cocaine, continually approaching and retreating from a site of self-administration. Moreover, rats develop conditioned place preference (CPP) for locations associated with the initial effects of cocaine, but develop aversion (CPA) for locations associated with subsequent negative effects. The ventral noradrenergic bundle is involved in animals' responses to aversive stimuli and projects to two amygdala structures—the central nucleus (CeA) and the basal nucleus of the stria terminalis (BNST)—linked to negative affect during drug withdrawal. Now Wenzel et al. report that noradrenergic signaling in CeA and BNST contributes to delayed aversive effects of acute cocaine. Injecting β-adrenergic antagonists into either area reduced retreat behaviors in the self-administration arena and reduced or reversed CPA for an environment associated with delayed effects of cocaine. In contrast, CPP for an environment associated with the initial effects of cocaine was unaffected.
Behavioral/Cognitive
Chronic Ethanol Reduces Dopamine Effects in mPFC
Heather Trantham-Davidson, Elizabeth J. Burnett, Justin T. Gass, Marcelo F. Lopez, Patrick J. Mulholland, et al.
(see pages 3706–3718)
Nearly all abused drugs, including alcohol, activate mesolimbic dopamine signaling. With repeated drug use, dopaminergic signaling is downregulated, leading to malaise, tolerance, and addiction. Dopamine has roles in many cognitive functions beyond the reward system, however, and these also become impaired with chronic drug use. Trantham-Davidson et al. found that rats exposed to chronic intermittent ethanol (CIE) for 2 weeks were slower than controls to learn new reward contingencies in a set-shifting task that assesses behavioral flexibility. This task depends on dopamine signaling in the medial prefrontal cortex (mPFC), and the impairment may have stemmed partly from loss of dopamine receptor signaling in this area. Activation of mPFC D2 receptors normally reduces electrically evoked firing in layer V pyramidal neurons while increasing evoked firing in fast-spiking interneurons; both these effects were absent in brain slices from CIE-exposed rats. In addition, CIE caused an increase in the amplitude of NMDA currents, and blocked the reduction of these currents by D2 receptor agonists.
