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Daniel R Storm

Publications and source records attributed to Daniel R Storm.

At least 37 records · Page 2Linked to original sources
PubMed2004

CRE-mediated gene transcription in the peri-infarct area after focal cerebral ischemia in mice.

Cyclic AMP response element binding protein (CREB) is a transcription factor expressed constitutively primarily in neurons and is activated by phosphorylation at Ser(133) residue. CREB mediates expression of several neuroprotective proteins, including B-cell CLL/lymphoma 2 (BCL-2) and brain-derived neurotrophic factor (BDNF). Although phosphorylation of CREB after ischemia has been investigated extensively, CRE-mediated gene transcription after ischemia is not as well studied. We investigated temporal changes in CRE-mediated gene transcription in the cerebral cortex after focal ischemia in transgenic mice with a CRE-lacZ reporter gene. In the ischemic core, X-gal-positive cells, which reflected expression of the CRE-lacZ reporter gene, were observed rarely at any time point, though transient phosphorylation of CREB was detected. In contrast, the peri-infarct area showed a persistent increase in the number of X-gal-positive cells, of which more than half were positive for neuronal nuclei (NeuN). Our results suggest that CRE-mediated gene transcription, the pattern of which is not always consistent with that of CREB phosphorylation, occurs primarily in neurons in the peri-infarct area after focal cerebral ischemia and may be a neuroprotective response against ischemic insult.

Animals↗
PubMed2004

Removal of G(ialpha1) constraints on adenylyl cyclase in the hippocampus enhances LTP and impairs memory formation.

Stimulation of adenylyl cyclase in the hippocampus is critical for memory formation. However, generation of cAMP signals within an optimal range for memory may require a balance between stimulatory and inhibitory mechanisms. The role of adenylyl cyclase inhibitory mechanisms for memory has not been addressed. One of the mechanisms for inhibition of adenylyl cyclase is through activation of G(i)-coupled receptors, a mechanism that could serve as a constraint on memory formation. Here we report that ablation of G(ialpha1) by gene disruption increases hippocampal adenylyl cyclase activity and enhances LTP in area CA1. Furthermore, gene ablation of G(ialpha1) or antisense oligonucleotide-mediated depletion of G(ialpha1) disrupted hippocampus-dependent memory. We conclude that G(ialpha1) provides a critical mechanism for tonic inhibition of adenylyl cyclase activity in the hippocampus. We hypothesize that loss of G(ialpha1) amplifies the responsiveness of CA1 postsynaptic neurons to stimuli that strengthen synaptic efficacy, thereby diminishing synapse-specific plasticity required for new memory formation.

Adenylyl Cyclases↗
PubMed2004

Isoform-specific knockout of FE65 leads to impaired learning and memory.

FE65 is a multimodular adapter protein that is expressed predominantly in brain. Its C-terminal phosphotyrosine interaction domain (PID) binds to the intracellular tail of the beta-amyloid precursor protein (betaPP), a protein of central importance to the pathogenesis of dementias of the Alzheimer type. To study the physiological functions of FE65, we generated a line of FE65 knockout mice via gene targeting. By Western analysis with a panel of FE65-specific antibodies, we demonstrate that the 97-kDa full-length FE65 (p97) was ablated in the mutant mice, and that a previously undescribed FE65 isoform with apparent molecular mass of 60 kDa (p60) was expressed in both wild-type and mutant mice. p60 had a truncated N-terminus and was likely to be generated through alternative translation. Expressions of the two isoforms appeared to be brain region distinct and age dependent. The p97FE65(-/-) mice were viable and showed no obvious physical impairments or histopathological abnormalities. However, p97FE65(-/-) and p97FE65(+/-) mice exhibited poorer performances than wild-type mice on a passive avoidance task when tested at 14 months (P <.05). p97FE65(-/-) mice at 14 months also exhibited impaired hidden-platform acquisition (P <.05) and a severe reversal-learning deficit (P <.002) but normal visual-platform acquisition in the Morris water maze tests. Probe trials confirmed impairments in p97FE65(-/-) mice in relearning of new spatial information, suggesting a hippocampus-dependent memory-extinction deficit. Reduced secretion of Abeta peptides was observed in primary neuronal cultures of hybrids of p97FE65(-/-)/betaPP transgenic (Tg2576) mice. These studies suggest an important and novel function of FE65 in learning and memory.

Aging↗
PubMed2004

Altered hippocampal short-term plasticity and associative memory in synaptotagmin IV (-/-) mice.

Synaptotagmin IV (Syt IV) is an activity-inducible, secretory vesicle protein that is thought to function as an inhibitor of neurotransmitter release (Littleton et al. Nature 400:757-760, 1999). To test this hypothesis in neurons of the mammalian CNS, we measured field excitatory postsynaptic potentials (fEPSPs) in hippocampal slice preparations from Syt IV (-/-) mice. At Schaffer collateral synapses, the basal properties of neurotransmission are largely normal. However, two forms of short-term plasticity, paired-pulse facilitation (PPF) and post-tetanic potentiation (PTP), are significantly enhanced in area CA1 of Syt IV (-/-) slices. Similarly, the early stages of long-term potentiation (LTP) are also enhanced at these synapses. Consistent with the low levels of Syt IV observed in dentate granule cells, the mossy fiber synapses in Syt IV (-/-) slices display largely normal PPF and LTP. In addition, we find that Syt IV (-/-) mice have deficits in the associative passive avoidance memory paradigm, but are normal in the novel object recognition paradigm. The synaptic architecture and connectivity of Syt IV (-/-) brains is indistinguishable from wild-type mice as indicated by immunohistochemical analysis. These results suggest Syt IV is a presynaptic negative regulator of short-term plasticity in area CA1 of the hippocampus and is required for some, but not all, forms of hippocampus-dependent memory.

Animals↗
PubMed2004

Reduced anxiety and depression-like behavior in synaptotagmin IV (-/-) mice.

Synaptotagmin IV (Syt IV) is a secretory vesicle protein that is broadly expressed in brain and may function as a presynaptic regulator of synaptic release. Because Syt IV and abnormalities in neurotransmission have been implicated in psychiatric disease, we examined Syt IV (-/-) mice in animal models of mood-related behavior. We report that Syt IV (-/-) mice display lower levels of anxiety-like behavior in the elevated plus maze and enhanced locomotion in the open field. Syt IV (-/-) mice also exhibit reduced depression-like behavior and are highly sensitive to the effects of the anti-depressant imipramine in a modified Porsolt forced swim test. However, the physical restraint-induced stress hormone response is normal in Syt IV (-/-) mice. As judged by immunohistochemical criteria, the synaptic structure and connectivity of the hippocampus and raphe nucleus in Syt IV (-/-) mice are indistinguishable from wild-type littermates. These results indicate that Syt IV plays a role in rodent mood-related behavior and suggests Syt IV regulates synaptic function in the neuronal networks that modulate these behaviors.

Animals↗
PubMed2004

Detection of odorants through the main olfactory epithelium and vomeronasal organ of mice.

Previous research has indicated that volatile odorants are detected through the main olfactory epithelium (MOE), whereas pheromones are detected via the vomeronasal organ (VNO). Gene disruption studies have established that olfactory signaling through the MOE is mediated through receptor stimulation of type 3 adenylyl cyclase (AC3). Mice lacking AC3 cannot detect odorants through the MOE. Recently, it was discovered using olfactory-based behavioral assays that AC3 mutant mice can detect some volatile odorants. An analysis of these mutant mice led to the surprising discovery that some odorants are detected through the VNO.

Adenylyl Cyclases↗
PubMed2004

Why calcium-stimulated adenylyl cyclases?

The Ca(2+)/calmodulin-stimulated adenylyl cyclases, AC1 and AC8, play a critical role in several forms of neuroplasticity, including long-lasting long-term potentiation (L-LTP) and long-term memory (LTM). By coupling neuronal activity and Ca(2+) increases to the production of cAMP, AC1 and AC8 activate cAMP-dependent signal transduction and transcriptional pathways critical for L-LTP and LTM.

Adenylyl Cyclases↗
PubMed2003

Type 8 adenylyl cyclase is targeted to excitatory synapses and required for mossy fiber long-term potentiation.

Mossy fiber/CA3 long-term potentiation (LTP) is hypothesized to depend on cAMP signals generated by Ca2+-stimulated adenylyl cyclases AC1 or AC8. AC1 gene knock-out mice (AC1-/-) show a partial reduction in mossy fiber LTP, suggesting that either AC8 activity is also critical for mossy fiber LTP or that there is a component of mossy fiber LTP that is independent of CaM-activated adenylyl cyclases. To address this issue, mossy fiber LTP was examined in hippocampal slices from AC8-/- and AC1-/- x AC8-/- double knock-out mice (DKO). Despite the fact that AC8 contributes only a small fraction of the Ca2+-stimulated adenylyl cyclase activity in the hippocampus and is less sensitive to Ca2+ than AC1, AC8-/- mice exhibited mossy fiber LTP defects comparable with AC1-/- and DKO mice. Furthermore, short-term plasticity was disrupted in AC8-/- mice but not in AC1-/- mice. Because AC1 is not localized at the excitatory synapses in hippocampal neurons, we hypothesized that AC8 may be targeted to synapses, in which higher synaptic-specific Ca2+ increases occur. Here, we report that AC8 accumulates in puncta of dendrites and axons in hippocampal neurons and colocalizes with synaptic marker proteins. These data indicate that both synaptic and nonsynaptic cAMP signals, generated by different Ca2+-stimulated adenylyl cyclases, are required for mossy fiber LTP.

Adenylyl Cyclases↗
PubMed2003

Brain-derived neurotrophic factor protection of cortical neurons from serum withdrawal-induced apoptosis is inhibited by cAMP.

Programmed cell death plays an important role both during the development of the CNS and in its homeostasis throughout adulthood. A complex balance between cell death- and survival-inducing signals determines the fate of individual neurons. Intracellular cAMP is thought to regulate neuronal survival, and previous studies have shown that the survival of retinal ganglion cells by brain-derived neurotrophic factor (BDNF) is dependent on cAMP. Here we report the surprising observation that cAMP attenuates the ability of BDNF to rescue cortical neurons from apoptosis after serum deprivation, a process mediated via the phosphatidylinositol 3 (PI3)-kinase signal transduction cascade. Depolarization by KCl, which increases cAMP in cortical neurons, also attenuates BDNF protection against serum withdrawal. Our data indicate that cAMP antagonizes neurotrophin protection from serum withdrawal by inhibiting the PI3-kinase signal transduction cascade. This study indicates that cAMP may inhibit some forms of neurotrophin-mediated neuronal survival and suggests that a number of PI3-kinase-regulated processes in neurons may be inhibited by cAMP.

Animals↗
PubMed2003

Vomeronasal organ detects odorants in absence of signaling through main olfactory epithelium.

It is commonly assumed that odorants are detected by the main olfactory epithelium (MOE) and pheromones are sensed through the vomeronasal organ (VNO). The complete loss of MOE-mediated olfaction in type-3 adenylyl cyclase knockout mice (AC3-/-) allowed us to examine chemosensory functions of the VNO in the absence of signaling through the MOE. Here we report that AC3-/- mice are able to detect certain volatile odorants via the VNO. These same odorants elicited electro-olfactogram transients in the VNO and MOE of wild-type mice, but only VNO responses in AC3-/- mice. This indicates that some odorants are detected through an AC3-independent pathway in the VNO.

Adenylyl Cyclases↗
PubMed2003

Calmodulin-regulated adenylyl cyclases: cross-talk and plasticity in the central nervous system.

Gene disruption studies have shown that the Ca(2+)-stimulated adenylyl cyclases, AC1 and AC8, are critical for some forms of synaptic plasticity, including long-term potentiation as well as long-term memory formation (LTM). It is hypothesized that these enzymes are required for LTM to support the increased expression of a family of genes regulated through the cAMP/Ca(2+) response element-binding protein/cAMP response element transcriptional pathway. In contrast to AC1 and AC8, AC3 is a Ca(2+)-inhibited adenylyl cyclase that plays an essential role in olfactory signal transduction. Coupling of odorant receptors to AC3 stimulates cAMP transients that function as the major second messenger for olfactory signaling. These cAMP transients are caused, at least in part, by Ca(2+) inhibition of AC3, which is mediated through calmodulin-dependent protein kinase II. The unique structure and regulatory properties of these adenylyl cyclases make them attractive drug target sites for modulation of a number of physiological processes including memory formation and olfaction.

Adenylyl Cyclases↗
PubMed2002

Genetic elimination of behavioral sensitization in mice lacking calmodulin-stimulated adenylyl cyclases.

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 in tests of acute pain, whereas behavioral responses to peripheral injection of two inflammatory stimuli, formalin and complete Freund's adjuvant, were reduced or abolished in AC1&8 DKO mice. AC1 and AC8 are highly expressed in the anterior cingulate cortex (ACC), and contribute to inflammation-induced activation of CREB. Intra-ACC administration of forskolin rescued behavioral allodynia defective in the AC1&8 DKO mice. Our studies suggest that AC1 and AC8 in the ACC selectively contribute to behavioral allodynia.

Adenylyl Cyclases↗
PubMed2002

CREB activity in the nucleus accumbens shell controls gating of behavioral responses to emotional stimuli.

The transcription factor cAMP response element (CRE)-binding protein (CREB) has been shown to regulate neural plasticity. Drugs of abuse activate CREB in the nucleus accumbens, an important part of the brain's reward pathways, and local manipulations of CREB activity have been shown to affect cocaine reward, suggesting an active role of CREB in adaptive processes that follow exposure to drugs of abuse. Using CRE-LacZ reporter mice, we show that not only rewarding stimuli such as morphine, but also aversive stimuli such as stress, activate CRE-mediated transcription in the nucleus accumbens shell. Using viral-mediated gene transfer to locally alter the activity of CREB, we show that this manipulation affects morphine reward, as well as the preference for sucrose, a more natural reward. We then show that local changes in CREB activity induce a more general syndrome, by altering reactions to anxiogenic, aversive, and nociceptive stimuli as well. Increased CREB activity in the nucleus accumbens shell decreases an animal's responses to each of these stimuli, whereas decreased CREB activity induces an opposite phenotype. These results show that environmental stimuli regulate CRE-mediated transcription within the nucleus accumbens shell, and that changes in CREB activity within this brain area subsequently alter gating between emotional stimuli and their behavioral responses. This control appears to be independent of the intrinsic appetitive or aversive value of the stimulus. The potential relevance of these data to addiction and mood disorders is discussed.

Animals↗
PubMed2002

A new form of cerebellar long-term potentiation is postsynaptic and depends on nitric oxide but not cAMP.

Long-term depression (LTD) at cerebellar parallel fiber (PF)-Purkinje cell synapses must be balanced by long-term potentiation (LTP) to prevent saturation and allow reversal of motor learning. The only previously analyzed form of cerebellar LTP is induced by 4-8 Hz PF stimulation and requires cAMP but not nitric oxide. It is a poor candidate to reverse LTD because it is presynaptically expressed whereas LTD is postsynaptic. We now characterize a new form of LTP induced by 1 Hz PF stimulation for at least 300 s. This LTP is postsynaptically expressed, enhanced by chelating postsynaptic Ca(2+), and depends on nitric oxide but not cAMP or cGMP, making it a plausible anti-Hebbian counterpart to Hebbian LTD.

Animals↗
PubMed2002

Phosphorylation of CBP mediates transcriptional activation by neural activity and CaM kinase IV.

Activity-regulated transcription has been implicated in adaptive plasticity in the CNS. In many instances, this plasticity depends upon the transcription factor CREB. Precisely how neuronal activity regulates CREB remains unclear. To address this issue, we examined the phosphorylation state of components of the CREB transcriptional pathway. We show that NMDA activates transcription of CREB-responsive genes in hippocampal neurons, with ERK responsible for persistent CREB phosphorylation and CaM kinase IV (CaMKIV) responsible for phosphorylating the CREB coactivator, CBP. Ser301 of CBP was identified as a major target of CaMKIV phosphorylation in vitro and in vivo. CaM kinase inhibitors attenuated phosphorylation at Ser301 and blocked CBP-dependent transcription. Additionally, mutation of Ser301 impaired NMDA- and CaMKIV-stimulated transcription. These findings demonstrate that activity-induced CaMKIV signaling contributes to CREB/CBP-dependent transcription by phosphorylating CBP at Ser301.

Amino Acid Sequence↗
PubMed2002

CaRF: a neuronal transcription factor that CaREs.

In this issue of Neuron, report the discovery of a new transcription factor, CaRF, that contributes to calcium stimulation of the BDNF gene through CaRE1, one of several calcium response elements found in the promoter of the BDNF gene. The CaRF/CaRE1 transcriptional pathway may control the expression of genes critical for activity-dependent, long-term changes in the central nervous system (CNS).

Animals↗
PubMed2002

Identification of a novel gene on chromosome 7q11.2 interrupted by a translocation breakpoint in a pair of autistic twins.

We report here the identification and characterization of a novel gene (AUTS2) that spans the 7q11.2 breakpoint in a monozygotic twin pair concordant for autism and a t(7;20) (q11.2; p11.2) translocation. AUTS2 is 1.2 Mb and has 19 exons. The predicted protein is 1295 amino acids and does not correspond to any known protein. DNA sequence analysis of autism subjects and controls revealed 22 biallelic polymorphic sites. For all sites, both alleles were observed in both cases and controls. Thus no autism-specific mutation was observed. Association analysis with two exonic polymorphic sites and linkage analysis of four dinucleotide repeat markers, two within and two flanking AUTS2, was negative. Thus, although it is unlikely that AUTS2 is an autism susceptibility gene for idiopathic autism, it may be the gene responsible for the disorder in the twins studied here.

Amino Acid Sequence↗