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J Neurosci [journal]
- ER-Mitochondrial Calcium Flow Underlies Vulnerability of Mechanosensory Hair Cells to Damage. [Journal Article]
- J Neurosci 2014 Jul 16; 34(29):9703-19.
Mechanosensory hair cells are vulnerable to environmental insult, resulting in hearing and balance disorders. We demonstrate that directional compartmental flow of intracellular Ca(2+) underlies death in zebrafish lateral line hair cells after exposure to aminoglycoside antibiotics, a well characterized hair cell toxin. Ca(2+) is mobilized from the ER and transferred to mitochondria via IP3 channels with little cytoplasmic leakage. Pharmacological agents that shunt ER-derived Ca(2+) directly to cytoplasm mitigate toxicity, indicating that high cytoplasmic Ca(2+) levels alone are not cytotoxic. Inhibition of the mitochondrial transition pore sensitizes hair cells to the toxic effects of aminoglycosides, contrasting with current models of excitotoxicity. Hair cells display efficient ER-mitochondrial Ca(2+) flow, suggesting that tight coupling of these organelles drives mitochondrial activity under physiological conditions at the cost of increased susceptibility to toxins.
- Unmasking of spiral ganglion neuron firing dynamics by membrane potential and neurotrophin-3. [Journal Article]
- J Neurosci 2014 Jul 16; 34(29):9688-702.
Type I spiral ganglion neurons have a unique role relative to other sensory afferents because, as a single population, they must convey the richness, complexity, and precision of auditory information as they shape signals transmitted to the brain. To understand better the sophistication of spiral ganglion response properties, we compared somatic whole-cell current-clamp recordings from basal and apical neurons obtained during the first 2 postnatal weeks from CBA/CaJ mice. We found that during this developmental time period neuron response properties changed from uniformly excitable to differentially plastic. Low-frequency, apical and high-frequency basal neurons at postnatal day 1 (P1)-P3 were predominantly slowly accommodating (SA), firing at low thresholds with little alteration in accommodation response mode induced by changes in resting membrane potential (RMP) or added neurotrophin-3 (NT-3). In contrast, P10-P14 apical and basal neurons were predominately rapidly accommodating (RA), had higher firing thresholds, and responded to elevation of RMP and added NT-3 by transitioning to the SA category without affecting the instantaneous firing rate. Therefore, older neurons appeared to be uniformly less excitable under baseline conditions yet displayed a previously unrecognized capacity to change response modes dynamically within a remarkably stable accommodation framework. Because the soma is interposed in the signal conduction pathway, these specializations can potentially lead to shaping and filtering of the transmitted signal. These results suggest that spiral ganglion neurons possess electrophysiological mechanisms that enable them to adapt their response properties to the characteristics of incoming stimuli and thus have the capacity to encode a wide spectrum of auditory information.
- Long-term plasticity in the regulation of olfactory bulb activity by centrifugal fibers from piriform cortex. [Journal Article]
- J Neurosci 2014 Jul 16; 34(29):9677-87.
Olfactory bulb granule cells are activated synaptically via two main pathways. Mitral/tufted (M/T) cells form dendrodendritic synapses on granule cells that can be activated by antidromic stimulation of the lateral olfactory tract (LOT). Centrifugal fibers originating from the association fiber (AF) system in piriform cortex (PC) make axodendritic synapses on granule cells within the granule cell layer (GCL) that can be activated by orthodromic stimulation of AF axons in the PC. We explored functional plasticity in the AF pathway by recording extracellularly from individual M/T cells and presumed granule cells in male Long-Evans rats under urethane anesthesia while testing their response to LOT and AF stimulation. Presumed granule cells driven synaptically by LOT stimulation (type L cells) were concentrated in the superficial half of the GCL and were activated at short latencies, whereas those driven synaptically by AF stimulation (type A cells) were concentrated in the deep half of the GCL and were activated at longer latencies. Type A cells were readily detected only in animals in which the AF input to the GCL had been previously potentiated by repeated high-frequency stimulation. An additional bout of high-frequency stimulation administered under urethane caused an immediate increase in the number of action potentials evoked in type A cells by AF test stimulation and a concomitant increase in inhibition of M/T cells. These results underscore the importance of the role played in olfactory processing by PC regulation of OB activity and document the long-lasting potentiation of that regulation by repeated high-frequency AF activation.
- Hypoactivation of CRF Receptors, Predominantly Type 2, in the Medial-Posterior BNST Is Vital for Adequate Maternal Behavior in Lactating Rats. [Journal Article]
- J Neurosci 2014 Jul 16; 34(29):9665-76.
Maternal behavior ensures the proper development of the offspring. In lactating mammals, maternal behavior is impaired by stress, the physiological consequence of central corticotropin-releasing factor receptor (CRF-R) activation. However, which CRF-R subtype in which specific brain area(s) mediates this effect is unknown. Here we confirmed that an intracerebroventricularly injected nonselective CRF-R antagonist enhances, whereas an agonist impairs, maternal care. The agonist also prolonged the stress-induced decrease in nursing, reduced maternal aggression and increased anxiety-related behavior. Focusing on the bed nucleus of the stria terminalis (BNST), CRF-R1 and CRF-R2 mRNA expression did not differ in virgin versus lactating rats. However, CRF-R2 mRNA was more abundant in the posterior than in the medial BNST. Pharmacological manipulations within the medial-posterior BNST showed that both CRF-R1 and CRF-R2 agonists reduced arched back nursing (ABN) rapidly and after a delay, respectively. After stress, both antagonists prevented the stress-induced decrease in nursing, with the CRF-R2 antagonist actually increasing ABN. During the maternal defense test, maternal aggression was abolished by the CRF-R2, but not the CRF-R1, agonist. Anxiety-related behavior was increased by the CRF-R1 agonist and reduced by both antagonists. Both antagonists were also effective in virgin females but not in males, revealing a sexual dimorphism in the regulation of anxiety within the medial-posterior BNST. In conclusion, the detrimental effects of increased CRF-R activation on maternal behavior are mediated via CRF-R2 and, to a lesser extent, via CRF-R1 in the medial-posterior BNST in lactating rats. Moreover, both CRF-R1 and CRF-R2 regulate anxiety in females independently of their reproductive status.
- Layer 6 corticothalamic neurons activate a cortical output layer, layer 5a. [Journal Article]
- J Neurosci 2014 Jul 16; 34(29):9656-64.
Layer 6 corticothalamic neurons are thought to modulate incoming sensory information via their intracortical axons targeting the major thalamorecipient layer of the neocortex, layer 4, and via their long-range feedback projections to primary sensory thalamic nuclei. However, anatomical reconstructions of individual layer 6 corticothalamic (L6 CT) neurons include examples with axonal processes ramifying within layer 5, and the relative input of the overall population of L6 CT neurons to layers 4 and 5 is not well understood. We compared the synaptic impact of L6 CT cells on neurons in layers 4 and 5. We found that the axons of L6 CT neurons densely ramified within layer 5a in both visual and somatosensory cortices of the mouse. Optogenetic activation of corticothalamic neurons generated large EPSPs in pyramidal neurons in layer 5a. In contrast, excitatory neurons in layer 4 exhibited weak excitation or disynaptic inhibition. Fast-spiking parvalbumin-positive cells in both layer 5a and layer 4 were also strongly activated by L6 CT neurons. The overall effect of L6 CT activation was to suppress layer 4 while eliciting action potentials in layer 5a pyramidal neurons. Together, our data indicate that L6 CT neurons strongly activate an output layer of the cortex.
- A hybrid electrical/chemical circuit in the spinal cord generates a transient embryonic motor behavior. [Journal Article]
- J Neurosci 2014 Jul 16; 34(29):9644-55.
Spontaneous network activity is a highly stereotyped early feature of developing circuits throughout the nervous system, including in the spinal cord. Spinal locomotor circuits produce a series of behaviors during development before locomotion that reflect the continual integration of spinal neurons into a functional network, but how the circuitry is reconfigured is not understood. The first behavior of the zebrafish embryo (spontaneous coiling) is mediated by an electrical circuit that subsequently generates mature locomotion (swimming) as chemical neurotransmission develops. We describe here a new spontaneous behavior, double coiling, that consists of two alternating contractions of the tail in rapid succession. Double coiling was glutamate-dependent and required descending hindbrain excitation, similar to but preceding swimming, making it a discrete intermediary developmental behavior. At the cellular level, motoneurons had a distinctive glutamate-dependent activity pattern that correlated with double coiling. Two glutamatergic interneurons, CoPAs and CiDs, had different activity profiles during this novel behavior. CoPA neurons failed to show changes in activity patterns during the period in which double coiling appears, whereas CiD neurons developed a glutamate-dependent activity pattern that correlated with double coiling and they innervated motoneurons at that time. Additionally, double coils were modified after pharmacological reduction of glycinergic neurotransmission such that embryos produced three or more rapidly alternating coils. We propose that double coiling behavior represents an important transition of the motor network from an electrically coupled spinal cord circuit that produces simple periodic coils to a spinal network driven by descending chemical neurotransmission, which generates more complex behaviors.
- Prolonged Adenosine A1 Receptor Activation in Hypoxia and Pial Vessel Disruption Focal Cortical Ischemia Facilitates Clathrin-Mediated AMPA Receptor Endocytosis and Long-Lasting Synaptic Inhibition in Rat Hippocampal CA3-CA1 Synapses: Differential Regulation of GluA2 and GluA1 Subunits by p38 MAPK and JNK. [Journal Article]
- J Neurosci 2014 Jul 16; 34(29):9621-43.
Activation of presynaptic adenosine A1 receptors (A1Rs) causes substantial synaptic depression during hypoxia/cerebral ischemia, but postsynaptic actions of A1Rs are less clear. We found that A1Rs and GluA2-containing AMPA receptors (AMPARs) form stable protein complexes from hippocampal brain homogenates and cultured hippocampal neurons from Sprague Dawley rats. In contrast, adenosine A2A receptors (A2ARs) did not coprecipitate or colocalize with GluA2-containing AMPARs. Prolonged stimulation of A1Rs with the agonist N(6)-cyclopentyladenosine (CPA) caused adenosine-induced persistent synaptic depression (APSD) in hippocampal brain slices, and APSD levels were blunted by inhibiting clathrin-mediated endocytosis of GluA2 subunits with the Tat-GluA2-3Y peptide. Using biotinylation and membrane fractionation assays, prolonged CPA incubation showed significant depletion of GluA2/GluA1 surface expression from hippocampal brain slices and cultured neurons. Tat-GluA2-3Y peptide or dynamin inhibitor Dynasore prevented CPA-induced GluA2/GluA1 internalization. Confocal imaging analysis confirmed that functional A1Rs, but not A2ARs, are required for clathrin-mediated AMPAR endocytosis in hippocampal neurons. Pharmacological inhibitors or shRNA knockdown of p38 MAPK and JNK prevented A1R-mediated internalization of GluA2 but not GluA1 subunits. Tat-GluA2-3Y peptide or A1R antagonist 8-cyclopentyl-1,3-dipropylxanthine also prevented hypoxia-mediated GluA2/GluA1 internalization. Finally, in a pial vessel disruption cortical stroke model, a unilateral cortical lesion compared with sham surgery reduced hippocampal GluA2, GluA1, and A1R surface expression and also caused synaptic depression in hippocampal slices that was consistent with AMPAR downregulation and decreased probability of transmitter release. Together, these results indicate a previously unknown mechanism for A1R-induced persistent synaptic depression involving clathrin-mediated GluA2 and GluA1 internalization that leads to hippocampal neurodegeneration after hypoxia/cerebral ischemia.
- Enhancing astrocytic lysosome biogenesis facilitates aβ clearance and attenuates amyloid plaque pathogenesis. [Journal Article]
- J Neurosci 2014 Jul 16; 34(29):9607-20.
In sporadic Alzheimer's disease (AD), impaired Aβ removal contributes to elevated extracellular Aβ levels that drive amyloid plaque pathogenesis. Extracellular proteolysis, export across the blood-brain barrier, and cellular uptake facilitate physiologic Aβ clearance. Astrocytes can take up and degrade Aβ, but it remains unclear whether this function is insufficient in AD or can be enhanced to accelerate Aβ removal. Additionally, age-related dysfunction of lysosomes, the major degradative organelles wherein Aβ localizes after uptake, has been implicated in amyloid plaque pathogenesis. We tested the hypothesis that enhancing lysosomal function in astrocytes with transcription factor EB (TFEB), a master regulator of lysosome biogenesis, would promote Aβ uptake and catabolism and attenuate plaque pathogenesis. Exogenous TFEB localized to the nucleus with transcriptional induction of lysosomal biogenesis and function in vitro. This resulted in significantly accelerated uptake of exogenously applied Aβ42, with increased localization to and degradation within lysosomes in C17.2 cells and primary astrocytes, indicating that TFEB is sufficient to coordinately enhance uptake, trafficking, and degradation of Aβ. Stereotactic injection of adeno-associated viral particles carrying TFEB driven by a glial fibrillary acidic protein promoter was used to achieve astrocyte-specific expression in the hippocampus of APP/PS1 transgenic mice. Exogenous TFEB localized to astrocyte nuclei and enhanced lysosome function, resulting in reduced Aβ levels and shortened half-life in the brain interstitial fluid and reduced amyloid plaque load in the hippocampus compared with control virus-injected mice. Therefore, activation of TFEB in astrocytes is an effective strategy to restore adequate Aβ removal and counter amyloid plaque pathogenesis in AD.
- N-Cadherin Promotes Recruitment and Migration of Neural Progenitor Cells from the SVZ Neural Stem Cell Niche into Demyelinated Lesions. [Journal Article]
- J Neurosci 2014 Jul 16; 34(29):9590-606.
Discrete cellular microenvironments regulate stem cell pools and their development, as well as function in maintaining tissue homeostasis. Although the signaling elements modulating neural progenitor cells (NPCs) of the adult subventricular zone (SVZ) niche are fairly well understood, the pathways activated following injury and the resulting outcomes, are less clear. In the present study, we used mouse models of demyelination and proteomics analysis to identify molecular cues present in the adult SVZ niche during injury, and analyzed their role on NPCs in the context of promoting myelin repair. Proteomic analysis of SVZ tissue from mice with experimental demyelination identified several proteins that are known to play roles in NPC proliferation, adhesion, and migration. Among the proteins found to be upregulated were members of the N-cadherin signaling pathway. During the onset of demyelination in the subcortical white matter (SCWM), activation of epidermal growth factor receptor (EGFR) signaling in SVZ NPCs stimulates the interaction between N-cadherin and ADAM10. Upon cleavage and activation of N-cadherin signaling by ADAM10, NPCs undergo cytoskeletal rearrangement and polarization, leading to enhanced migration out of the SVZ into demyelinated lesions of the SCWM. Genetically disrupting either EGFR signaling or ADAM10 inhibits this pathway, preventing N-cadherin regulated NPC polarization and migration. Additionally, in vivo experiments using N-cadherin gain- and loss-of-function approaches demonstrated that N-cadherin enhances the recruitment of SVZ NPCs into demyelinated lesions. Our data revealed that EGFR-dependent N-cadherin signaling physically initiated by ADAM10 cleavage is the response of the SVZ niche to promote repair of the injured brain.
- CREB SUMOylation by the E3 Ligase PIAS1 Enhances Spatial Memory. [Journal Article]
- J Neurosci 2014 Jul 16; 34(29):9574-89.
cAMP-responsive element binding protein (CREB) phosphorylation and signaling plays an important role in long-term memory formation, but other posttranslational modifications of CREB are less known. Here, we found that CREB1Δ, the short isoform of CREB, could be sumoylated by the small ubiquitin-like modifier (SUMO) E3 ligase protein inhibitor of activated STAT1 (PIAS1) at Lys271 and Lys290 and PIAS1 SUMOylation of CREB1Δ increased the expression level of CREB1Δ. CREB1Δ could also be sumoylated by other PIAS family proteins, but not by the E3 ligases RanBP2 and Pc2 or by the E2 ligase Ubc9. Furthermore, water maze training increased the level of endogenous CREB SUMOylation in rat CA1 neurons determined by in vitro SUMOylation assay, but this effect was not observed in other brain areas. Moreover, transduction of Lenti-CREBWT to rat CA1 area facilitated, whereas transduction of Lenti-CREB double sumo-mutant (CREBK271RK290R) impaired, spatial learning and memory performance. Transduction of Lenti-CREBWT-SUMO1 fusion vector to rat CA1 area showed a more significant effect in enhancing spatial learning and memory and CREB SUMOylation. Lenti-CREBWT transduction increased, whereas Lenti-CREBK271RK290R transduction decreased, CREB DNA binding to the brain-derived neurotrophic factor (bdnf) promoter and decreased bdnf mRNA expression. Knock-down of PIAS1 expression in CA1 area by PIAS1 siRNA transfection impaired spatial learning and memory and decreased endogenous CREB SUMOylation. In addition, CREB SUMOylation was CREB phosphorylation dependent and lasted longer. Therefore, CREB phosphorylation may be responsible for signal transduction during the early phase of long-term memory formation, whereas CREB SUMOylation sustains long-term memory.