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GABARAP recognizes and binds the γ2 subunit of the GABAA receptor, interacts with microtubules and the N-ethyl maleimide sensitive factor, and is proposed to function in GABAA receptor trafficking and postsynaptic localization. We have determined the crystal structure of human GABARAP at 1.6 Å resolution. The structure comprises an N-terminal helical subdomain and a ubiquitin-like C-terminal domain...
What we see depends on where we look. This paper characterizes the modulatory effects of point of regard in three-dimensional space on responsiveness of visual cortical neurons in areas V1, V2, and V4. Such modulatory effects are both common, affecting 85% of cells, and strong, frequently producing changes of mean firing rate by a factor of 10. The prevalence of neurons in area V4 showing a preference...
Repertoires of grooming behaviors critical to survival are exhibited by most animal species, including humans. Genes that influence this complex behavior are unknown. We report that mice with disruptions of Hoxb8 show, with 100% penetrance, excessive grooming leading to hair removal and lesions. Additionally, these mice excessively groom normal cagemates. We have been unable to detect any skin or...
Calcium-triggered exocytosis at the synapse is suppressed by addition of calcium chelators, but the effects of endogenous Ca2+ buffers have not been tested. We find that 80% of Ca2+ binding sites in the synaptic terminal of retinal bipolar cells were associated with mobile molecules that suppressed activation of Ca2+-sensitive K+ channels with an efficiency equivalent to ∼1.2 mM BAPTA. Removing these...
Excessive grooming behaviors, cleansing rituals, and self-mutilation are important features of a range of neuropsychiatric diseases including obsessive compulsive (OC)-spectrum disorders. In this issue of Neuron, Greer and Capecchi (2002) report that Hoxb8 mutant mice exhibit this behavioral phenotype. These Hoxb8 mutants will be valuable in exploring the genetics and pathophysiology of OC-spectrum...
At the cerebellar synapses between parallel fibers (PFs) and Purkinje cells (PCs), long-term depression (LTD) of the excitatory synaptic current has been assumed to be independent of the N-methyl-D-aspartate (NMDA) receptor activation because PCs lack NMDA receptors. However, we now report that LTD is suppressed by NMDA receptor antagonists that act on presynaptic NMDA receptors of the PFs. This effect...
Slit proteins have previously been shown to regulate axon guidance, branching, and neural migration. Here we report that, in addition to acting as a chemorepellant for cortical axons, Slit1 regulates dendritic development. Slit1 is expressed in the developing cortex, and exposure to Slit1 leads to increased dendritic growth and branching. Conversely, inhibition of Slit-Robo interactions by Robo-Fc...
GIRK (Kir3) channels are activated by neurotransmitters coupled to G proteins, via a direct binding of Gβγ. The role of Gα subunits in GIRK gating is elusive. Here we demonstrate that Gαi is not only a donor of Gβγ but also regulates GIRK gating. When overexpressed in Xenopus oocytes, GIRK channels show excessive basal activity and poor activation by agonist or Gβγ. Coexpression of Gαi3 or Gαi1 restores...
To permit direct functional analyses of neural circuits, we have developed a method for stimulating groups of genetically designated neurons optically. Coexpression of the Drosophila photoreceptor genes encoding arrestin-2, rhodopsin (formed by liganding opsin with retinal), and the α subunit of the cognate heterotrimeric G protein—an explosive combination we term “chARGe”—sensitizes generalist vertebrate...
The family of neurotrophic factors known as neurotrophins has yielded a series of surprises, both with regard to the broad extent of their functional roles and the remarkable complexity of their signaling mechanisms. The recent discovery that a neurotrophin precursor protein and its proteolytically processed products may differentially activate pro- and antiapoptotic cellular responses, through preferential...
The cellular and molecular mechanisms that guide axonal and dendritic differentiation in the cerebral cortex are just beginning to be defined. Many of the molecular signals that guide axons also, and sometimes simultaneously, influence dendritic growth. Whitford et al. (2002)([this issue of Neuron]) demonstrate that in addition to their roles in axon guidance and cell migration cue, Slit proteins...
Modulation of Ca2+ channels by neurotransmitters provides critical control of neuronal excitability and synaptic strength. Little is known about regulation of the Ca2+ efflux pathways that counterbalance Ca2+ influx in neurons. We demonstrate that bradykinin and ATP significantly facilitate removal of action potential-induced Ca2+ loads by stimulating plasma membrane Ca2+-ATPases (PMCAs) in rat sensory...
Different classes of photoreceptor neurons (R cells) in the Drosophila compound eye form connections in different optic ganglia. The R1-R6 subclass connects to the first optic ganglion, the lamina, and relies upon glial cells as intermediate targets. Conversely, R cells promote glial cell development including migration of glial cells into the target region. Here, we show that the JAB1/CSN5 subunit...
G protein-activated potassium channels (GIRKs), monitored with the temporal and molecular resolution of electrophysiology, play a key role in the study of signal transduction. GIRKs are activated primarily by the Gβγ subunits, but a paper by Peleg et al. (2002)([this issue of Neuron]) demonstrates a role for Gα subunits in suppressing basal activity and supports the idea of a macromolecular complex...
Coyle et al. (2002), in this issue of Neuron, reveal the crystal structure for the GABAA receptor binding protein, GABARAP. They show GABARAP can switch from a monomer to an extended linear polymer form that may function to assemble microtubules during the intracellular trafficking or postsynaptic clustering of GABAA receptors.
Many N-methyl-D-aspartate receptor (NMDAR) channel blockers that have therapeutic potential can be trapped in the closed state. Using a combination of the substituted cysteine accessibility method and open channel blockers, we found that the M3 segment forms the core of the extracellular vestibule, including a deep site for trapping blockers. The M3 segment, as well as more superficial parts of the...
We model the development of the functional circuit of layer 4 (the input-recipient layer) of cat primary visual cortex. The observed thalamocortical and intracortical circuitry codevelop under Hebb-like synaptic plasticity. Hebbian development yields opponent inhibition: inhibition evoked by stimuli anticorrelated with those that excite a cell. Strong opponent inhibition enables recognition of stimulus...
In this issue of Neuron, Tsui-Pierchala et al. (2002) show that in rodent SCG neurons NGF activates Ret, the signaling component of the multisubunit GDNF receptor, in vitro and in vivo by a mechanism, which is independent of GFL ligands and GFRα coreceptors. NGF-dependent Ret phosphorylation regulates soma size and metabolism but not survival of maturing postnatal sympathetic neurons.
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