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The unfolded protein response (UPR) is a eukaryotic signaling pathway linking protein flux through the endoplasmic reticulum to transcription and translational repression. Herein, we demonstrate UPR activation in the leukodystrophy Pelizaeus-Merzbacher disease (PMD) as well as in three mouse models of this disease and transfected fibroblasts expressing mutant protein. The CHOP protein, widely known...
The neural mechanisms by which fear is inhibited are poorly understood at the present time. Behaviorally, a conditioned fear response may be reduced in intensity through a number of means. Among the simplest of these is extinction, a form of learning characterized by a decrease in the amplitude and frequency of a conditioned response when the conditioned stimulus that elicits it is repeatedly nonreinforced...
Rod signals reach ganglion cells via at least five pathways. A new study in this issue of Neuron shows that all pathways from rods to ON-type ganglion cells require connexin36. This is the first physiological demonstration in mammals that a well-defined neural circuit requires a gap junction as an obligatory transmission step.
Proteins that bind to the cytoplasmic tails of AMPA receptors control receptor trafficking and thus the strength of postsynaptic responses. Here we show that AP2, a clathrin adaptor complex important for endocytosis, associates with a region of GluR2 that overlaps the NSF binding site. Peptides used previously to interfere with NSF binding also antagonize GluR2-AP2 interaction. Using GluR2 mutants...
Activity-dependent and -independent signals collaborate to regulate synaptogenesis, but their relative contributions are unclear. Here, we describe the formation of neuromuscular synapses at which neurotransmission is completely and specifically blocked by mutation of the neurotransmitter-synthesizing enzyme choline acetyltransferase. Nerve terminals differentiate extensively in the absence of neurotransmitter,...
In this issue of Neuron, Zhang and Poo present evidence for localized BDNF-induced synaptic potentiation that is accompanied by spatially restricted calcium influx and requires local axonal protein synthesis. These results are consistent with a synapse-specific role for BDNF and provide a potentially novel way to think about cellular mechanisms for potentiation of neurotransmitter release.
Brain-derived neurotrophic factor (BDNF) is known to promote neuronal survival, guide axonal pathfinding, and participate in activity-dependent synaptic plasticity. In Xenopus nerve-muscle cultures, localized contact of a single BDNF-coated bead with the presynaptic axon resulted in potentiation of transmitter secretion at the developing synapses, but only when the bead was placed within 60 μm from...
Two components of cortical circuits could mediate contour integration in primary visual cortex (V1): intrinsic horizontal connections and feedback from higher cortical areas. To distinguish between these, we combined functional mapping with a new technique for labeling axons, a recombinant adenovirus bearing the gene for green fluorescent protein (GFP), to determine the extent, density, and orientation...
It is widely acknowledged that movements are planned at the level of the kinematics. However, the central nervous system must ultimately transform kinematic plans into dynamics-related commands. How, when, and where the kinematics-to-dynamics (KD) transformation is processed represent fundamental and unanswered questions. We recorded from the supplementary motor area (SMA) of two monkeys as they executed...
Brain drug development of either small molecule or large molecule (recombinant proteins, gene medicines) neurotherapeutics has been limited, owing to the restrictive transport properties of the brain microvasculature, which forms the blood-brain barrier (BBB) in vivo. Widespread drug delivery to the brain, while not feasible via craniotomy and intracerebral injection, is possible if the drug is delivered...
We used electron tomography of frog saccular hair cells to reconstruct presynaptic ultrastructure at synapses specialized for sustained transmitter release. Synaptic vesicles at inhibited synapses were abundant in the cytoplasm and covered the synaptic body at high density. Continuous maximal stimulation depleted 73% of the vesicles within 800 nm of the synapse, with a concomitant increase in surface...
Adenylyl cyclase types 1 (AC1) and 8 (AC8), the two major calmodulin-stimulated adenylyl cyclases in the brain, couple NMDA receptor activation to cAMP signaling pathways. Cyclic AMP signaling pathways are important for many brain functions, such as learning and memory, drug addiction, and development. Here we show that wild-type, AC1, AC8, or AC1&8 double knockout (DKO) mice were indistinguishable...
Mammalian neurogenesis is determined by an interplay between intrinsic genetic mechanisms and extrinsic cues such as growth factors. Here we have defined a signaling cascade, a MEK-C/EBP pathway, that is essential for cortical progenitor cells to become postmitotic neurons. Inhibition of MEK or of the C/EBP family of transcription factors inhibits neurogenesis while expression of a C/EBPβ mutant that...
We used fear conditioning, which is known to alter synaptic efficacy in lateral amygdala (LA), to study molecular mechanisms underlying long-term memory. Following fear conditioning, the tyrosine phosphorylated protein p190 RhoGAP becomes associated with GRB2 in LA significantly more in conditioned than in control rats. RasGAP and Shc were also found to associate with GRB2 in LA significantly more...
Chemical genetics is an emerging technology for revealing the signaling networks that regulate biological phenotypes using exogenous reagents such as small organic molecules. To study neurobiology using chemical genetics, high-throughput cell and organismal assays can be created to identify compounds and proteins that regulate diverse neuronal phenotypes, such as cell viability, gene expression level,...
We demonstrate that Drosophila capulet (capt), a homolog of the adenylyl cyclase-associated protein that binds and regulates actin in yeast, associates with Abl in Drosophila cells, suggesting a functional relationship in vivo. We find a robust and specific genetic interaction between capt and Abl at the midline choice point where the growth cone repellent Slit functions to restrict axon crossing...
To examine the functions of electrical synapses in the transmission of signals from rod photoreceptors to ganglion cells, we generated connexin36 knockout mice. Reporter expression indicated that connexin36 was present in multiple retinal neurons including rod photoreceptors, cone bipolar cells, and AII amacrine cells. Disruption of electrical synapses between adjacent AIIs and between AIIs and ON...
Chemical genetics, or the specific modulation of cellular systems by small molecules, has complemented classical genetic analysis throughout the history of neurobiology. We outline several of its contributions to the understanding of ion channel biology, heat and cold signal transduction, sleep and diurnal rhythm regulation, effects of immunophilin ligands, and cell surface oligosaccharides with respect...
In Drosophila photoreceptors, the amplification responsible for generating quantum bumps in response to photoisomerization of single rhodopsin molecules has been thought to be mediated downstream of phospholipase C (PLC), since bump amplitudes were reportedly unaffected in mutants with greatly reduced levels of either G protein or PLC. We now find that quantum bumps in such mutants are reduced ∼3-...
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