Localization and behaviors in null mice suggest that ASIC1 and ASIC2 modulate responses to aversive stimuli

Abstract

Acid sensing ion channels (ASICs) generate H+-gated Na+ currents that contribute to neuronal function and animal behavior. Like ASIC1, ASIC2 subunits are expressed in the brain and multimerize with ASIC1 to influence acid-evoked currents and facilitate ASIC1 localization to dendritic spines. To better understand how ASIC2 contributes to brain function, we localized the protein and tested the behavioral consequences of ASIC2 gene disruption. For comparison, we also localized ASIC1 and studied ASIC1−/− mice. ASIC2 was prominently expressed in areas of high synaptic density, and with a few exceptions, ASIC1 and ASIC2 localization exhibited substantial overlap. Loss of ASIC1 or ASIC2 decreased freezing behavior in contextual and auditory cue fear conditioning assays, in response to predator odor, and in response to CO2 inhalation. In addition, loss of ASIC1 or ASIC2 increased activity in a forced swim assay. These data suggest that ASIC2, like ASIC1, plays a key role in determining the defensive response to aversive stimuli. They also raise the question of whether gene variations in both ASIC1 and ASIC2 might affect fear and panic in humans.

Two aspects of ASIC function: Synaptic plasticity and neuronal injury

“…These mRNA expression data are consistent with the immunlocalizaiton studies (Coryell et al, 2009; Price et al, 2014; Wemmie et al, 2003). Some regions, e.g., amygdala, somatosensory cortex, posterior cingular cortex, dentate gyrus in hippocampus, show higher levels of ASIC1a expression than others.…”

“…For a review of ASIC1a expression in the nervous system, see (Zha, 2013). One recent study performed a thorough immunolocalization analysis of ASIC2 in the brain, and compared it side-by-side with that of ASIC1a (Price et al, 2014). The result shows that the expression of ASIC2 and ASIC1a proteins overlaps in most brain regions, with synaptically dense regions exhibit high staining of both ASIC1a and ASIC2.…”

“…One interesting observation is that ASIC1a and ASIC2 exhibit high levels of expression in “fear structures” such as amygdala and bed nucleus of the stria terminalis (BNST) (Coryell et al, 2007; Price et al, 2014; Wemmie et al, 2003). These data suggest an important role of ASICs in fear and related behavior.…”

Protons are a neurotransmitter that regulates synaptic plasticity in the lateral amygdala

“…We studied lateral amygdala brain slices because amygdala-dependent fear-related behavior depends on a pH reduction (36). In addition, ASICs are abundantly expressed there, and ASIC1a −/− mice have impaired fearlike behavior (36)(37)(38).…”

Determinants of action of hydrophobic amines on ASIC1a and ASIC2a

“…The aim of the present study was to reveal principal structural determinants of action of amine-containing compounds on ASIC1a and ASIC2a, which are predominantly expressed in central nervous system of vertebrates (Wemmie et al, 2003;Coryell et al, 2009;Price et al, 2014) and can form functional homomers. We selected 17 compounds, which are structurally related to the first four previously studied monoamines.…”