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Daniel R Storm

Publications and source records attributed to Daniel R Storm.

At least 19 recordsLinked to original sources
PubMed2007

Ca2+ -stimulated adenylyl cyclases regulate ERK-dependent activation of MSK1 during fear conditioning.

The cAMP and ERK/MAP kinase (MAPK) signal transduction pathways are critical for hippocampus-dependent memory, a process that depends on CREB-mediated transcription. However, the extent of crosstalk between these pathways and the downstream CREB kinase activated during memory formation has not been elucidated. Here we report that PKA, MAPK, and MSK1, a CREB kinase, are coactivated in a subset of hippocampal CA1 pyramidal neurons following contextual fear conditioning. Activation of PKA, MAPK, MSK1, and CREB is absolutely dependent on Ca(2+)-stimulated adenylyl cyclase activity. We conclude that adenylyl cyclase activity supports the activation of MAPK, and that MSK1 is the major CREB kinase activated during training for contextual memory.

Adenylyl Cyclases↗
PubMed2006

Calmodulin-stimulated adenylyl cyclase gene deletion affects morphine responses.

To define the roles of the calmodulin-stimulated adenylyl cyclases (AC1 and AC8) in morphine-induced analgesia, tolerance, physical dependence, and conditioned place preference, we used mice having targeted disruptions of either the AC1 or AC8 genes or both genes [double knockout mice (DKO)]. Mice lacking either AC1 or AC8 genes or DKO did not differ from wild-type mice in short-term antinociceptive responses to morphine measured in the tail-flick analgesia assay. Morphine tolerance that developed immediately within 3 h of morphine administration (10 mg/kg s.c.) was significantly attenuated in DKO mice and AC8 single knockout mice. Tolerance induced continually by daily injections of morphine (10 mg/kg s.c.) was also reduced in DKO mice. In DKO mice continually treated with morphine, there was a significant reduction in withdrawal behaviors, including reduced wet-dog shakes and forepaw tremor after naloxone injection (10 mg/kg i.p.). Morphine produced hyperlocomotion and conditioned place preference in wild-type mice, whereas DKO mice displayed significantly less hyperlocomotion and conditioned place preference. Furthermore, the significant increase in phosphorylated cAMP-response element binding protein (CREB) staining in ventral tegmental area induced by long-term morphine treatment was not evident in DKO mice, suggesting that CREB activation by morphine requires cAMP generated by AC1 and AC8. These results support the hypothesis that calmodulin-stimulated adenylyl cyclases are important mediators of the neuronal responses to morphine.

Adenylyl Cyclases↗
PubMed2006

Pheromone detection in male mice depends on signaling through the type 3 adenylyl cyclase in the main olfactory epithelium.

Terrestrial vertebrates have evolved two anatomically and mechanistically distinct chemosensory structures: the main olfactory epithelium (MOE) and the vomeronasal organ (VNO). Although it has been generally thought that pheromones are detected through the VNO, whereas other chemicals are sensed by the MOE, recent evidence suggests that some pheromones may be detected through the MOE. Odorant receptors in the MOE are coupled to the type 3 adenylyl cyclase (AC3), an enzyme not expressed in the VNO. Consequently, odorants and pheromones do not elicit electrophysiological responses in the MOE of AC3-/- mice, although VNO function is intact. Here we report that AC3-/- mice cannot detect mouse milk, urine, or mouse pheromones. Inter-male aggressiveness and male sexual behaviors are absent in AC3-/- mice. Furthermore, adenylyl cyclase activity in membranes prepared from the MOE of wild-type mice, but not AC3-/- mice, is stimulated by 2-heptanone, a mouse pheromone. We conclude that signaling through AC3 in the MOE is obligatory for male sexual behavior, male-male aggressiveness, and the detection of some pheromones.

Adenylyl Cyclases↗
PubMed2006

Rookie snail protein LAPS veteran C/EBP: net transcriptional proceeds for long-term facilitation.

Long-term changes in synaptic plasticity require new protein synthesis. This preview discusses data from Kim et al. (this issues of Neuron) that demonstrate the requirement of a novel, nucleolar protein, LLP (LAPS18-like protein), for the formation of long-term facilitation in Aplysia. LLP binds to and transcriptionally activates C/EBP, thereby promoting the formation of long-term facilitation and behavioral sensitization.

Animals↗
PubMed2006

Role of the calcium modulated cyclases in the development of the retinal projections.

Transmembrane isoforms of adenylate cyclases (AC) integrate a wide variety of extracellular signals from neurotransmitters to morphogens and can also regulate cAMP production in response to calcium entry. Based on observations in the barrelless mouse strain, the Adcy1 gene (AC1) was involved in the segregation of binocular retinal inputs. To determine the potential role of other AC isoforms we localized the Adcy genes in the visual centres during development, using in situ hybridization. Six different AC subtypes were found in the developing retinal ganglion cell layer (RGC; AC1, AC2, AC3, AC5, AC8, and AC9), and three AC subtypes were expressed in the central brain targets, the dorsal lateral geniculate nucleus (AC1 and AC8), the ventral lateral geniculate nucleus (AC2 and AC8) and the superior colliculus (AC1, AC2, AC8). Using a genetic approach we tested the role of the calcium modulated cyclases AC1, AC5 and AC8 for the segregation retinal fibres. Ipsilateral retinal axons remained exuberant in the AC1(-/-) mice, with overlapping retinal projections from both eyes in the superior colliculus and the visual thalamus. These abnormalities were similar to those of barrelless mouse mutants. No abnormalities were detectable in the AC5(-/-) or the AC8(-/-) mice. Similar abnormalities were noted in the single AC1(-/-) and the AC1/AC8 double-knockout mice (DKO). Thus, only AC1 is required for the maturation of the retinal axon terminals whereas AC5 and AC8 are not needed. The specificity of AC1's action is linked to its cellular localization in the RGCs and to its distinctive functional profile, compared with the other cyclases expressed in the same cells.

Adenylyl Cyclases↗
PubMed2005

Role of hippocampal Cav1.2 Ca2+ channels in NMDA receptor-independent synaptic plasticity and spatial memory.

Current knowledge about the molecular mechanisms of NMDA receptor (NMDAR)-independent long-term potentiation (LTP) in the hippocampus and its function for memory formation in the behaving animal is limited. NMDAR-independent LTP in the CA1 region is thought to require activity of postsynaptic L-type voltage-dependent Ca2+ channels (Cav1.x), but the underlying channel isoform remains unknown. We evaluated the function of the Cav1.2 L-type Ca2+ channel for spatial learning, synaptic plasticity, and triggering of learning-associated biochemical processes using a mouse line with an inactivation of the CACNA1C (Cav1.2) gene in the hippocampus and neocortex (Cav1.2(HCKO)). This model shows (1) a selective loss of protein synthesis-dependent NMDAR-independent Schaffer collateral/CA1 late-phase LTP (L-LTP), (2) a severe impairment of hippocampus-dependent spatial memory, and (3) decreased activation of the mitogen-activated protein kinase (MAPK) pathway and reduced cAMP response element (CRE)-dependent transcription in CA1 pyramidal neurons. Our results provide strong evidence for a role of L-type Ca2+ channel-dependent, NMDAR-independent hippocampal L-LTP in the formation of spatial memory in the behaving animal and for a function of the MAPK/CREB (CRE-binding protein) signaling cascade in linking Cav1.2 channel-mediated Ca2+ influx to either process.

2-Amino-5-phosphonovalerate↗
PubMed2005

Hippocampal neurons express a calcineurin-activated adenylyl cyclase.

Ca2+-stimulated adenylyl cyclases are important for several forms of neuroplasticity because they couple activity-dependent Ca2+ increases to cAMP in neurons. For example, the calmodulin-stimulated adenylyl cyclases, AC1 and AC8, are required for hippocampus-dependent memory and long-lasting long-term potentiation. To identify other mechanisms for Ca2+ stimulation of adenylyl cyclases, cultured hippocampal neurons from transgenic mice lacking both AC1 and AC8 [double knock-out (DKO) mice] were analyzed for Ca2+ stimulation of intracellular cAMP. Surprisingly, neurons from DKO mice showed significant Ca2+-stimulated cAMP accumulation that was blocked by inhibitors of calcineurin [PP2B (protein phosphatase 2B)], a Ca2+-activated protein phosphatase. Analysis of cultured neurons from calcineurin(-/-) mice confirmed that hippocampal neurons exhibit a calcineurin-dependent cAMP increase, which may contribute to some forms of neuroplasticity.

Adenylyl Cyclases↗
PubMed2005

The dosage of the neuroD2 transcription factor regulates amygdala development and emotional learning.

The amygdala is centrally involved in formation of emotional memory and response to fear or risk. We have demonstrated that the lateral and basolateral amygdala nuclei fail to form in neuroD2 null mice and neuroD2 heterozygotes have fewer neurons in this region. NeuroD2 heterozygous mice show profound deficits in emotional learning as assessed by fear conditioning. Unconditioned fear was also diminished in neuroD2 heterozygotes compared to wild-type controls. Several key molecular regulators of emotional learning were diminished in the brains of neuroD2 heterozygotes including Ulip1, alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor, and GABA(A) receptor. Thus, neuroD2 is essential for amygdala development and genes involved in amygdala function are altered in neuroD2-deficient mice.

Amygdala↗
PubMed2005

Odorant-induced activation of extracellular signal-regulated kinase/mitogen-activated protein kinase in the olfactory bulb promotes survival of newly formed granule cells.

Extracellular signal-regulated kinase 1/2 (Erk1/2)/mitogen-activated protein (MAP) kinase (MAPK) plays a significant role in neuronal survival, including odorant-induced, activity-dependent survival of olfactory sensory neurons in the main olfactory epithelium. Here, we examined the role of MAPK for the survival of neurons in the olfactory bulb. To study odorant-induced activation of MAPK in the olfactory bulb, mice were exposed to odorants in vivo, and MAPK was assayed. Exposure of mice to some odorants in vivo activated MAPK in granule cells 10 min after exposure. Activation of MAPK was particularly evident in the nucleus and dendrites of granule cells. Because MAPK activation can augment neuronal survival, odorant enhancement of granule cell survival was monitored by bromodeoxyuridine (BrdU) incorporation. Long-term exposure to odorants increased the survival of newly formed granule cells as well as the number of granule cells that were both BrdU+ and phospho-Erk+. Inhibition of MAPK by administration of SL327 in vivo blocked the odorant-induced increase in newly formed granule cells, suggesting that activation of MAPK promotes the survival of granule cells in the olfactory bulb. Studies using cultured granule cells confirmed that activation of MAPK in granule cells protects them against strong apoptotic signals. These data suggest that stimulation of MAPK in olfactory bulb granule cells by some odorants may contribute to the survival of newly formed granule cells caused by odorant exposure.

Aminoacetonitrile↗
PubMed2005

Calcium-stimulated adenylyl cyclases are critical modulators of neuronal ethanol sensitivity.

The importance of the cAMP signaling pathway in the modulation of ethanol sensitivity has been suggested by studies in organisms from Drosophila melanogaster to man. However, the involvement of specific isoforms of adenylyl cyclase (AC), the molecule that converts ATP to cAMP, has not been systemically determined in vivo. Because AC1 and AC8 are the only AC isoforms stimulated by calcium, and ethanol modulates calcium flux by the NMDA receptor, we hypothesized that these ACs would be important in the neural response to ethanol. AC1 knock-out (KO) mice and double knock-out (DKO) mice with genetic deletion of both AC1 and AC8 display substantially increased sensitivity to ethanol-induced sedation compared with wild-type (WT) mice, whereas AC8 KO mice are only minimally more sensitive. In contrast, AC8 KO and DKO mice, but not AC1 KO mice, demonstrate decreased voluntary ethanol consumption compared with WT mice. DKO mice do not display increased sleep time compared with WT mice after administration of ketamine or pentobarbital, indicating that the mechanism of enhanced ethanol sensitivity in these mice is likely distinct from the antagonism of ethanol of the NMDA receptor and potentiation of the GABA(A) receptor. Ethanol does not enhance calcium-stimulated AC activity, but the ethanol-induced phosphorylation of a discrete subset of protein kinase A (PKA) substrates is compromised in the brains of DKO mice. These results indicate that the unique activation of PKA signaling mediated by the calcium-stimulated ACs is an important component of the neuronal response to ethanol.

Adenylyl Cyclases↗
PubMed2005

PI3 kinase signaling is required for retrieval and extinction of contextual memory.

Memory retrieval is a dynamic aspect of memory formation that can be studied separately from other stages of memory processing. Although several signal transduction pathways including ERK/MAP kinase have been implicated in memory retrieval, the underlying signaling events are poorly defined. Here we report that re-exposure of mice to context after contextual training stimulates the activity of phosphatidylinositol 3 kinase (PI3K) in the hippocampus. Inhibition of PI3K activity in the hippocampus in vivo blocked contextual memory retrieval and extinction. Inhibitors of PI3K signaling also blocked increases in ERK/MAP kinase activity associated with memory retrieval. This suggests that PI3K activation in the hippocampus is critical for memory retrieval and is required for activation of ERK/MAP kinase during retrieval.

Animals↗
PubMed2005

The role of calmodulin as a signal integrator for synaptic plasticity.

Excitatory synapses in the brain show several forms of synaptic plasticity, including long-term potentiation (LTP) and long-term depression (LTD), which are initiated by increases in intracellular Ca(2+) that are generated through NMDA (N-methyl-D-aspartate) receptors or voltage-sensitive Ca(2+) channels. LTP depends on the coordinated regulation of an ensemble of enzymes, including Ca(2+)/calmodulin-dependent protein kinase II, adenylyl cyclase 1 and 8, and calcineurin, all of which are stimulated by calmodulin, a Ca(2+)-binding protein. In this review, we discuss the hypothesis that calmodulin is a central integrator of synaptic plasticity and that its unique regulatory properties allow the integration of several forms of signal transduction that are required for LTP and LTD.

Animals↗
PubMed2004

Requirement for the RIIbeta isoform of PKA, but not calcium-stimulated adenylyl cyclase, in visual cortical plasticity.

The cAMP-dependent protein kinase (PKA) signaling pathway plays a key role in visual cortical plasticity. Inhibitors that block activation of all PKA regulatory subunits (RIalpha,RIbeta, RIIalpha, RIIbeta) abolish long-term potentiation (LTP) and long-term depression (LTD) in vitro and ocular dominance plasticity (ODP) in vivo. The details of this signaling cascade, however, including the source of PKA signals and which PKA subunits are involved, are unknown. To investigate these issues we have examined LTP, LTD, and ODP in knock-out mice lacking either the two cortically expressed Ca2+-stimulated adenylyl cyclases (AC1 and AC8) or the predominant neocortical subunit of PKA (RIIbeta). Here we show that plasticity remains intact in AC1/AC8-/- mice, whereas ODP and LTD, but not LTP, are absent in RIIbeta-/- mice. We conclude that (1) plasticity in the visual cortex does not require the activity of known Ca2+-stimulated adenylyl cyclases, (2) the PKA dependence of ODP and LTD, but not LTP, is mediated by RIIbeta-PKA, and (3) multiple isoforms of PKA contribute to LTD.

Adenylyl Cyclases↗
PubMed2004

Overexpression of type-1 adenylyl cyclase in mouse forebrain enhances recognition memory and LTP.

Cyclic AMP is a positive regulator of synaptic plasticity and is required for several forms of hippocampus-dependent memory including recognition memory. The type I adenylyl cyclase, Adcy1 (also known as AC1), is crucial in memory formation because it couples Ca(2+) to cyclic AMP increases in the hippocampus. Because Adcy1 is neurospecific, it is a potential pharmacological target for increasing cAMP specifically in the brain and for improving memory. We have generated transgenic mice that overexpress Adcy1 in the forebrain using the Camk2a (also known as alpha-CaMKII) promoter. These mice showed elevated long-term potentiation (LTP), increased memory for object recognition and slower rates of extinction for contextual memory. The increase in recognition memory and lower rates of contextual memory extinction may be due to enhanced extracellular signal-related kinase (ERK)/mitogen-activated protein kinase (MAPK) signaling, which is elevated in mice that overexpress Adcy1.

Adenylyl Cyclases↗
PubMed2004

Odorant stimulation enhances survival of olfactory sensory neurons via MAPK and CREB.

Olfactory sensory neurons (OSNs) can be sensitized to odorants by repeated exposure, suggesting that an animal's responsiveness to olfactory cues can be enhanced at the initial stage of detection. However, because OSNs undergo a regular cycle of apoptosis and replacement by ostensibly naive, precursor-derived neurons, the advantage of sensitization would be lost in the absence of a mechanism for odorant-enhanced survival of OSNs. Using recombinant adenoviruses in conjunction with surgical and electrophysiological techniques, we monitored OSN survival and function in vivo and find that odorant exposure selectively rescues populations of OSNs from apoptosis. We further demonstrate that odorant stimuli rescue OSNs in a cAMP-dependent manner by activating the MAPK/CREB-dependent transcriptional pathway, possibly as a result of expression of Bcl-2.

Animals↗
PubMed2004

Gating of the cAMP signaling cascade and melatonin synthesis by the circadian clock in mammalian retina.

Melatonin is synthesized in retinal photoreceptor cells and acts as a neuromodulator imparting photoperiodic information to the retina. The synthesis of melatonin is controlled by an ocular circadian clock and by light in a finely tuned mechanism that ensures that melatonin is synthesized and acts only at night in darkness. Here we report that the circadian clock gates melatonin synthesis in part by regulating the expression of the type 1 adenylyl cyclase (AC1) and the synthesis of cAMP in photoreceptor cells. This gating is effected through E-box-mediated transcriptional activation of the AC1 gene, which undergoes robust daily fluctuations that persist in constant illumination. The circadian control of the cAMP signaling cascade indicates that the clock has a more general and profound impact on retinal functions than previously thought. In addition, rhythmic control of AC1 expression was observed in other parts of the central circadian axis, the suprachiasmatic nucleus and pineal gland, but not in other brain areas examined. Thus, clock control of the cAMP signaling cascade may play a central role in the integration of circadian signals that control physiology and behavior.

ARNTL Transcription Factors↗