Overexpression of acid-sensing ion channel 1a in transgenic mice increases acquired fear-related behavior

Wemmie, John A.; Coryell, Matthew W.; Askwith, Candice C.; Lamani, Ejvis; Leonard, A. Soren; Sigmund, Curt D.; Welsh, Michael J.

doi:10.1073/pnas.0308753101

Cited by 191 publications

(159 citation statements)

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“…6,7 ASIC1a in particular is involved in nociception and fear behavior triggered by hypercapnia. 8,9 ASICs have also been investigated as new targets for the treatment of ischemic stroke and cerebral hypoxia 10 on the premise that activation of ASIC1a during ischemia may cause neuronal cell death through toxic Ca 2 þ and Na þ influx. 10,11 Metabolic acidosis can occur as a result of lactate accumulation when tissue perfusion is inadequate, or when mitochondrial respiration is inhibited.…”

mentioning

confidence: 99%

Acidotoxicity and acid-sensing ion channels contribute to motoneuron degeneration

et al. 2013

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Amyotrophic lateral sclerosis (ALS) is a fatal neurological condition with no cure. Mitochondrial dysfunction, Ca 2 þ overloading and local hypoxic/ischemic environments have been implicated in the pathophysiology of ALS and are conditions that may initiate metabolic acidosis in the affected tissue. We tested the hypothesis that acidotoxicity and acid-sensing ion channels (ASICs) are involved in the pathophysiology of ALS. We found that motoneurons were selectively vulnerable to acidotoxicity in vitro, and that acidotoxicity was partially reduced in asic1a-deficient motoneuron cultures. Cross-breeding of SOD1 G93A ALS mice with asic1a-deficient mice delayed the onset and progression of motor dysfunction in SOD1 mice. Interestingly, we also noted a strong increase in ASIC2 expression in motoneurons of SOD1 mice and sporadic ALS patients during disease progression. Pharmacological pan-inhibition of ASIC channels with the lipophilic amiloride derivative, 5-(N,N-dimethyl)-amiloride hydrochloride, potently protected cultured motoneurons against acidotoxicity, and, given post-symptom onset, significantly improved lifespan, motor performance and motoneuron survival in SOD1 mice. Together, our data provide strong evidence for the involvement of acidotoxicity and ASIC channels in motoneuron degeneration, and highlight the potential of ASIC inhibitors as a new treatment approach for ALS. Cell Death and Differentiation (2013) 20, 589-598; doi:10.1038/cdd.2012.158; published online 11 January 2013Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative condition where motoneurons in the spinal cord and brain stem die, resulting in paralysis and eventual death. Despite the significant recent advances in understanding the pathophysiology and genetics of ALS, 1 there is no cure for this condition. Currently, the only FDA-approved, disease-modifying drug used for the treatment of ALS is riluzole, which inhibits neuronal glutamate, releases and stimulates glutamate uptake into astrocytes. 2 The use of riluzole is based on the hypothesis that overactivation of Ca 2 þ -permeable AMPA receptors in motoneurons results in excitotoxicity, and that this process contributes to motoneuron death in ALS. 3 Nevertheless, the disease-modifying effects of riluzole therapy are moderate and vary among patients. 4 Acid-sensing ion channels (ASICs) represent a group of ion channels activated by protons. They belong to the epithelial sodium (Na þ ) family of amiloride-sensitive cation channels, and allow for Na þ and Ca 2 þ entry into neurons. Of the six ASIC subunits cloned, ASIC1a, ASIC2a and ASIC2b are expressed in the brain and spinal cord neurons. 5 ASIC1a and ASIC2s are found in the brain regions with high synaptic density and facilitate excitatory synaptic transmission. 6,7 ASIC1a in particular is involved in nociception and fear behavior triggered by hypercapnia. 8,9 ASICs have also been investigated as new targets for the treatment of ischemic stroke and cerebral hypoxia 10 on the premise that activation of ASIC1a during ischemia ...

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confidence: 99%

Acidotoxicity and acid-sensing ion channels contribute to motoneuron degeneration

et al. 2013

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“…It will be interesting to determine how these genes and their pathways interact, as many of the mechanisms underlying learning and memory appear to be conserved. For example, mammalian ASIC-1 is involved in learned fear (Wemmie et al 2004), and a SNP in casy-1 ortholog, calsyntenin-2, has been linked to human memory performance (Papassotiropoulos et al 2006).…”

Section: Resultsmentioning

confidence: 99%

“…The role of mammalian ASIC-1 in learning (Wemmie et al 2002(Wemmie et al , 2004 prompted Voglis and Tavernarakis (2008) to study its C. elegans homolog. They found that asic-1 mutants were impaired in isothermal tracking as well as associative learning assays pairing chemosensory cues with food or starvation.…”

Section: Asic-1mentioning

confidence: 99%

An elegant mind: Learning and memory in Caenorhabditis elegans

Ardiel¹,

Rankin²

2010

Learn. Mem.

281

191

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This article reviews the literature on learning and memory in the soil-dwelling nematode Caenorhabditis elegans. Paradigms include nonassociative learning, associative learning, and imprinting, as worms have been shown to habituate to mechanical and chemical stimuli, as well as learn the smells, tastes, temperatures, and oxygen levels that predict aversive chemicals or the presence or absence of food. In each case, the neural circuit underlying the behavior has been at least partially described, and forward and reverse genetics are being used to elucidate the underlying cellular and molecular mechanisms. Several genes have been identified with no known role other than mediating behavior plasticity.Historically, it was believed that even if they were capable of learning, the nervous systems of invertebrates were too different to be instructive on human cognition. In the 1960s, Kandel and colleagues began studying learning in the marine mollusc Aplysia (Kandel and Tauc 1965). Using this system, they were able to relate behavioral plasticity to changes at specific synapses of identified neurons, and began a biochemical analysis of these neuronal changes, uncovering a role for cAMP, PKA, and CREB. In the 1970s, Benzer and colleagues began a genetic dissection of learning in the fruit fly Drosophila melanogaster (Quinn et al. 1974;Dudai et al. 1976). They established an associative learning assay (Quinn et al. 1974) and conducted a forward genetic screen, identifying the first learning mutant, dunce (Dudai et al. 1976). Since then, many genes have been cloned, and the biological basis of learning has proven to be highly conserved (Barco et al. 2006;Skoulakis and Grammenoudi 2006). Today there is no question as to the relevance of invertebrate research in the field of learning and memory.At about the same time that Kandel was beginning his work with Aplysia, Sydney Brenner chose Caenorhabditis elegans as the organism in which to study development and the nervous system (Brenner 1974). Today this transparent nematode is the world's best understood animal. It's small size ( 1 mm), short life cycle (,3 d), and ease of cultivation make it perfect for the laboratory, and its mode of reproduction is ideal for genetic analysis-selffertilizing hermaphrodites can be easily inbred or crossed with males. The genome has been mapped and sequenced, and there are thousands of mutants and RNAi constructs readily available for researchers. Furthermore, C. elegans has an invariant cell lineage and relatively simple morphology-959 cells make up the entire adult hermaphrodite (Sulston and Horvitz 1977;Sulston et al. 1983). Using serial section electron micrographs, White et al. (1986) were able to construct a neural wiring diagram of the hermaphrodite's 302 neurons. They found about 5000 chemical synapses, 600 gap junctions, and 2000 neuromuscular junctions, the location of which were fairly consistent between animals. With its invariant cell lineage and reproducible connectome, C. elegans was initially viewed as a genetically hardwired ...

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“…A bioinformatic search of the chromosome segment comprising the 17q11.2-q12 region suggested the ACCN1 gene as the most interesting gene, as the acid-sensing ion channels (ASICs) may be involved in anxiety-related pathways. [25][26][27] The ACCN1 gene comprises a genomic region of approximately 1. Figure 1 An overview of the study design: in stage 1, we conducted a genome-wide scan, which detected significant association between PD and a twomarker segment (D17S1294-D17S1293) on chromosome 17.…”

Section: Genotypingmentioning

confidence: 99%

A genome-wide study of panic disorder suggests the amiloride-sensitive cation channel 1 as a candidate gene

et al. 2011

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Panic disorder (PD) is a mental disorder with recurrent panic attacks that occur spontaneously and are not associated to any particular object or situation. There is no consensus on what causes PD. However, it is recognized that PD is influenced by environmental factors, as well as genetic factors. Despite a significant hereditary component, genetic studies have only been modestly successful in identifying genes of importance for the development of PD. In this study, we conducted a genome-wide scan using microsatellite markers and PD patients and control individuals from the isolated population of the Faroe Islands. Subsequently, we conducted a fine mapping, which revealed the amiloride-sensitive cation channel 1 (ACCN1) located on chromosome 17q11.2-q12 as a potential candidate gene for PD. The further analyses of the ACCN1 gene using singlenucleotide polymorphisms (SNPs) revealed significant association with PD in an extended Faroese case-control sample. However, analyses of a larger independent Danish case-control sample yielded no substantial significant association. This suggests that the possible risk alleles associated in the isolated population are not those involved in the development of PD in a larger outbred population.

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Overexpression of acid-sensing ion channel 1a in transgenic mice increases acquired fear-related behavior

Cited by 191 publications

References 54 publications

Acidotoxicity and acid-sensing ion channels contribute to motoneuron degeneration

Acidotoxicity and acid-sensing ion channels contribute to motoneuron degeneration

An elegant mind: Learning and memory in Caenorhabditis elegans

A genome-wide study of panic disorder suggests the amiloride-sensitive cation channel 1 as a candidate gene

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