Acid-Sensing Ion Channel-1a in the Amygdala, a Novel Therapeutic Target in Depression-Related Behavior

Coryell, Matthew W.; Wunsch, Amanda M.; Haenfler, Jill M.; Allen, Jason E.; Schnizler, M.; Ziemann, Adam; Cook, Melloni N.; Dunning, Jonathan P.; Price, Margaret P.; Rainier, Jon D.; Liu, Zhuqing; Light, Alan R.; Langbehn, Douglas R.; Wemmie, John A.

doi:10.1523/jneurosci.0360-09.2009

Cited by 147 publications

(130 citation statements)

References 65 publications

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“…The anxiolytic function of ASIC1a, as suggested by the present results, contradicts previous studies showing that activation of ASIC1a, in mice, is necessary for the generation and expression of certain types of fear, and genetic elimination of these channels has anxiolytic effects Dwyer et al, 2009;Ziemann et al 2009). The discrepancy cannot be attributed to possible developmental alterations in the ASIC1a-null mice, as most of the results obtained in these mice were confirmed by intraventricular administration of ASIC1a antagonists in wild-type mice Dwyer et al, 2009;Ziemann et al 2009).…”

Section: Discussioncontrasting

confidence: 90%

“…The discrepancy cannot be attributed to possible developmental alterations in the ASIC1a-null mice, as most of the results obtained in these mice were confirmed by intraventricular administration of ASIC1a antagonists in wild-type mice Dwyer et al, 2009;Ziemann et al 2009). In the present study, we activated or inhibited ASIC1a by local injections into the BLA, which is a different situation from lacking ASIC1a or inhibiting ASIC1a throughout the brain.…”

Section: Discussionmentioning

confidence: 96%

“…The BLA displays a markedly high expression of the ASIC1a subunit (Wemmie et al, 2003;Coryell et al, 2007), but it also expresses the ASIC2a and ASIC2b subunits (Lingueglia et al, 1997;Biagini et al, 2001). It is unknown if the functional ASIC1a channels in the BLA are homomeric ASIC1a trimers, or if they coassemble with the ASIC2a or ASIC2b.…”

Section: Discussionmentioning

confidence: 99%

“…Fear and anxiety are associated with hyperactivity and hyperexcitability of the basolateral amygdala (BLA; Gonzalez et al, 1996;Sajdyk and Shekhar, 1997;Vazdarjanova et al, 2001;Shekhar et al, 2003;Braga et al, 2004;Gale et al, 2004;AroniadouAnderjaska et al, 2007;Zhou et al, 2010;Wang et al, 2011). It was not surprising, therefore, that localized ASIC1a expression in the BLA of ASIC1a-null mice restored the fear behavior induced by CO 2 inhalation (Ziemann et al, 2009). The implication of these behavioral studies is that the function of ASIC1a in the BLA is to promote hyperactivity.…”

Section: Introductionmentioning

confidence: 97%

“…However, behavioral studies seem to suggest that in the amygdala, a brain region that plays a central role in emotional behavior (Phelps and LeDoux, 2005) and associated disorders-such as anxiety disorders (Rauch et al, 2000;Shekhar et al, 2003;Etkin and Wager, 2007;Stein and Stein, 2008)-the function of the ASIC1a is to promote hyperexcitability, rather than to enhance inhibition. Thus, genetic elimination or pharmacological blockade of ASIC1a, in mice, reduces fear Ziemann et al, 2009) and has antidepressant ) and anxiolytic effects (Dwyer et al, 2009). Fear and anxiety are associated with hyperactivity and hyperexcitability of the basolateral amygdala (BLA; Gonzalez et al, 1996;Sajdyk and Shekhar, 1997;Vazdarjanova et al, 2001;Shekhar et al, 2003;Braga et al, 2004;Gale et al, 2004;AroniadouAnderjaska et al, 2007;Zhou et al, 2010;Wang et al, 2011).…”

Section: Introductionmentioning

confidence: 99%

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ASIC1a Activation Enhances Inhibition in the Basolateral Amygdala and Reduces Anxiety

et al. 2014

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The discovery that even small changes in extracellular acidity can alter the excitability of neuronal networks via activation of acid-sensing ion channels (ASICs) could have therapeutic application in a host of neurological and psychiatric illnesses. Recent evidence suggests that activation of ASIC1a, a subtype of ASICs that is widely distributed in the brain, is necessary for the expression of fear and anxiety. Antagonists of ASIC1a, therefore, have been proposed as a potential treatment for anxiety. The basolateral amygdala (BLA) is central to fear generation, and anxiety disorders are characterized by BLA hyperexcitability. To better understand the role of ASIC1a in anxiety, we attempted to provide a direct assessment of whether ASIC1a activation increases BLA excitability. In rat BLA slices, activation of ASIC1a by low pH or ammonium elicited inward currents in both interneurons and principal neurons, and increased spontaneous IPSCs recorded from principal cells significantly more than spontaneous EPSCs. Epileptiform activity induced by high potassium and low magnesium was suppressed by ammonium. Antagonism of ASIC1a decreased spontaneous IPSCs more than EPSCs, and increased the excitability of the BLA network, as reflected by the pronounced increase of evoked field potentials, suggesting that ASIC1a channels are active in the basal state. In vivo activation or blockade of ASIC1a in the BLA suppressed or increased, respectively, anxiety-like behavior. Thus, in the rat BLA, ASIC1a has an inhibitory and anxiolytic function. The discovery of positive ASIC1a modulators may hold promise for the treatment of anxiety disorders.

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Section: Discussioncontrasting

confidence: 90%

Section: Discussionmentioning

confidence: 96%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 97%

Section: Introductionmentioning

confidence: 99%

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ASIC1a Activation Enhances Inhibition in the Basolateral Amygdala and Reduces Anxiety

et al. 2014

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Putative Binding Sites, and Pathways to Them, for Amidine and Guanidine Current Inhibitors on Acid‐Sensing Ion Channels (ASIC). A Theoretical Approach with hASIC1a Homology Model

Pietra

2012

Chemistry & Biodiversity

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Central inhibition of the acid-sensing hASIC1a channel, acting upstream of the opiate system, might serve to treat any type of pain, avoiding the unwanted addiction problems of the opioid drugs. To this end, inhibition of hASIC1a channel by PcTx1, a peptide from the Trinidad chevron tarantula, is under development. New inhibitors of the hASIC1a channel are also being sought, in the hope of further modulating the activity, from which antiplasmodial amidine and guanidine phenyl drugs have emerged as promising candidates. However, how such current inhibition takes place remains obscure from the molecular point of view, hindering any further progress in developing drugs. Therefore, the nature of the binding sites, and how they are reached by the amidine-guanidine drugs, was investigated here via automated docking and molecular dynamics with hASIC1a homology models. This study has revealed that this ion channel is rich in binding sites, and that flexible drugs, such as nafamostat, may penetrate it in a snake-like elongated conformation. Then, crawling like a snake through temporary holes in the protein, nafamostat either simply flips, or changes to a high-energy folded conformation to become adapted to the shape of the binding site.

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The basolateral amygdala γ‐aminobutyric acidergic system in health and disease

Prager

Bergstrom

Wynn

et al. 2015

J of Neuroscience Research

143

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The brain comprises an excitatory/inhibitory neuronal network that maintains a finely tuned balance of activity critical for normal functioning. Excitatory activity in the basolateral amygdala (BLA), a brain region that plays a central role in emotion and motivational processing, is tightly regulated by a relatively small population of gamma-aminobutyric acid (GABA) inhibitory neurons. Disruption in GABAergic inhibition in the BLA can occur when there is a loss of local GABAergic interneurons, alterations in GABAA receptor activation, or dysregulation of mechanisms that modulate BLA GABAergic inhibition. Disruptions in GABAergic control of the BLA emerge during development, in aging populations, or after a trauma, ultimately resulting in hyperexcitability. BLA hyperexcitability manifests behaviorally as an increase in anxiety, emotional dysregulation, or the development of seizure activity. This article reviews the anatomy, development, and physiology of the GABAergic system in the BLA, and circuits that modulate GABAergic inhibition, including the dopaminergic, serotonergic, noradrenergic, and cholinergic systems. We highlight how alterations in various neurotransmitter receptors, including the acid sensing ion channel 1a (ASIC1a), cannabinoid receptor 1 (CB1), and glutamate receptor subtypes, expressed on BLA interneurons, modulate GABAergic transmission and how defects of these systems affects inhibitory tonus within the BLA. Finally, we discuss alterations in the BLA GABAergic system in neurodevelopmental (autism/Fragile X syndrome) and neurodegenerative (Alzheimer’s disease) diseases, and after the development of epilepsy, anxiety, and traumatic brain injury. A more complete understanding of the intrinsic excitatory/inhibitory circuit balance of the amygdala and how imbalances in inhibitory control contribute to excessive BLA excitability will guide the development of novel therapeutic approaches in neuropsychiatric diseases.

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Acid-Sensing Ion Channel-1a in the Amygdala, a Novel Therapeutic Target in Depression-Related Behavior

Cited by 147 publications

References 65 publications

ASIC1a Activation Enhances Inhibition in the Basolateral Amygdala and Reduces Anxiety

ASIC1a Activation Enhances Inhibition in the Basolateral Amygdala and Reduces Anxiety

Putative Binding Sites, and Pathways to Them, for Amidine and Guanidine Current Inhibitors on Acid‐Sensing Ion Channels (ASIC). A Theoretical Approach with hASIC1a Homology Model

The basolateral amygdala γ‐aminobutyric acidergic system in health and disease

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