Cellular/Molecular
Copper Suppresses Extrasynaptic GABAA Currents
Thomas P. McGee, Catriona M. Houston, and Stephen G. Brickley
(see pages 13431–13435)
Copper is present at high levels in the brain, where it serves as a cofactor for several intracellular enzymes. Copper is also present in synaptic vesicles, and when it is released during synaptic transmission it modulates the function of synaptic proteins, including glutamate and GABAA receptors. McGee et al. have discovered that GABAA receptors containing the δ subunit (δ-GABAARs)—which are expressed extrasynaptically and mediate tonic inhibition in some neurons—are much more sensitive to the inhibitory effects of copper than receptors containing the γ subunit (γ-GABAARs). Whereas 10 nm copper significantly reduced GABA-mediated currents in HEK cells expressing δ-GABAARs, 1 μm was required to produce detectable suppression in cells expressing γ-GABAARs. More importantly, 10 μm copper halved tonic inhibitory conductance in mouse cerebellar neurons without affecting synaptic currents. Chelating extracellular copper in cerebellar slices increased tonic inhibitory conductance, suggesting that copper normally suppresses these conductances. Because tonic inhibition regulates neuron excitability, copper may play a role in shaping neural activity.
Development/Plasticity/Repair
Par3 Phosphorylation Slows Axonal Specification
Yasuhiro Funahashi, Takashi Namba, Shin Fujisue, Norimichi Itoh, Shinichi Nakamuta, et al.
(see pages 13270–13285)
After exiting the cell cycle, newborn pyramidal neurons extend multiple processes before beginning to migrate to their final destinations. As migration commences, all but the leading and trailing process retract, and the remaining processes start to acquire characteristics of the apical dendrite and axon, respectively. Axon and dendrite specialization involves construction of distinct cytoskeletal structures and differential trafficking of membrane-associated and intracellular proteins, and it is shaped by extracellular cues and numerous downstream effectors. Several neurotrophic factors activate extracellular-signal-regulated kinase ERK2, which associates with Par3, a component of a protein complex involved in axon specification. Par3 binds to kinesin KIF3a and becomes concentrated distally in the nascent axon as hippocampal neurons polarize in culture. Funahashi et al. report that ERK2-mediated phosphorylation of Par3 occurred mainly in distal axons and inhibited Par3 interaction with KIF3a. A point mutation that mimicked this phosphorylation slowed transport of Par3 to the distal axon and slowed the establishment of polarity both in vitro and in vivo.
ERK 2 (left) associates with Par3 (right) in growth cones (labeled with phalloidin, blue) from rat hippocampal neurons in culture. See the article by Funahashi et al. for details.
Systems/Circuits
Melanocortins Affect Gut Motility via Hindbrain Receptors
Janell Richardson, Maureen T. Cruz, Usnish Majumdar, Amanda Lewin, Kathryn A. Kingsbury, et al.
(see pages 13286–13299)
The nucleus of the solitary tract (NTS) is a major player in the control of feeding. The NTS receives sensory information about taste and gut distension, responds to hormones secreted by the gut and adipose tissue, and receives projections from appetite-regulating regions of the hypothalamus. One target of NTS neurons is the dorsal motor vagal nucleus (DMVN), which projects to the stomach and regulates gastric motility. This, in turn, affects satiety by determining how quickly the stomach empties after a meal. Melanocortin peptides are major regulators of feeding, and type 4 melanocortin receptors (MC4Rs) are highly expressed in the NTS and DMVN. Richardson et al. found that injecting an endogenous melanocortin, α-melanocyte stimulating hormone (α-MSH), into rat NTS inhibited phasic stomach contractions and decreased gastric tone, which is expected to slow stomach emptying, prolong satiety, and reduce food consumption. In contrast, injecting α-MSH into the DMVN increased phasic gut contractions, which is expected to help grind food and speed emptying.
Neurobiology of Disease
Cortical Synaptic Density Is Reduced in a Depression Model
Ronald R. Seese, Lulu Y. Chen, Conor D. Cox, Daniela Schulz, Alex H. Babayan, et al.
(see pages 13441–13448)
Abnormal functioning of several neurotransmitter systems contributes to various forms of depression. In bipolar disorder, for example, markers of glutamatergic synapses are reduced in prefrontal cortex and fewer GABAergic inhibitory neurons are present in cingulate cortex. Markers of excitatory synapses are also reduced in rats bred to express learned helplessness (cLH), a model of depression. To determine whether this reduction stems from changes in the number or size of excitatory synapses, Seese et al. used fluorescence deconvolution tomography to assess the number, volume, and labeling intensity of ∼250,000 synapses in rat infralimbic cortex. Although the number of synapses labeled with the postsynaptic density protein PSD95 did not differ significantly between cLH rats and controls, the intensity was lower in cLH rats, suggesting PSD95 levels were reduced. In contrast, the number, but not intensity, of synapses expressing AMPA receptors was reduced in cLH rats. The number of synapses with GABAA receptors was also reduced in cLH rats, suggesting both inhibitory and excitatory transmission is abnormal.
