Acid-sensing ion channels 1a (ASIC1a) inhibit neuromuscular transmission in female mice

Acid-sensing ion channels (ASIC) open in response to extracellular acidosis. ASIC1a, a particular subtype of these channels, has been described to have a postsynaptic distribution in the brain, being involved not only in ischemia and epilepsy, but also in fear and psychiatric pathologies. High-frequency stimulation of skeletal motor nerve terminals (MNTs) can induce presynaptic pH changes in combination with an acidification of the synaptic cleft, known to contribute to muscle fatigue. Here, we studied the role of ASIC1a channels on neuromuscular transmission. We combined a behavioral wire hanging test with electrophysiology, pharmacological, and immunofluorescence techniques to compare wild-type and ASIC1a lacking mice (ASIC1a −/− knockout). Our results showed that 1) ASIC1a −/− female mice were weaker than wild type, presenting shorter times during the wire hanging test; 2) spontaneous neurotransmitter release was reduced by ASIC1a activation, suggesting a presynaptic location of these channels at individual MNTs; 3) ASIC1a-mediated effects were emulated by extracellular local application of acid saline solutions (pH = 6.0; HEPES/MES-based solution); and 4) immunofluorescence techniques revealed the presence of ASIC1a antigens on MNTs. These results suggest that ASIC1a channels might be involved in controlling neuromuscular transmission, muscle contraction and fatigue in female mice.Fil: Urbano Suarez, Francisco Jose. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Fisiología, Biología Molecular y Neurociencias. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Fisiología, Biología Molecular y Neurociencias; ArgentinaFil: Lino, Noelia Gisele. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Fisiología, Biología Molecular y Neurociencias. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Fisiología, Biología Molecular y Neurociencias; ArgentinaFil: González Inchauspe, Carlota María Fabiola. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Fisiología, Biología Molecular y Neurociencias. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Fisiología, Biología Molecular y Neurociencias; ArgentinaFil: Gonzalez, Laura Elisabeth. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Fisiología, Biología Molecular y Neurociencias. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Fisiología, Biología Molecular y Neurociencias; ArgentinaFil: Colettis, Natalia Claudia. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Fisiología, Biología Molecular y Neurociencias. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Fisiología, Biología Molecular y Neurociencias; ArgentinaFil: Vattino, Lucas Gabriel. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Fisiología, Biología Molecular y Neurociencias. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Fisiología, Biología Molecular y Neurociencias; ArgentinaFil: Wunsch, Amanda M.. University of Iowa; Estados UnidosFil: Wemmie, John A.. University of Iowa; Estados UnidosFil: Uchitel, Osvaldo Daniel. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Fisiología, Biología Molecular y Neurociencias. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Fisiología, Biología Molecular y Neurociencias; Argentin

The ins of the striatum: Utilizing chemogenetics to define the contribution of cortical and thalamic afferents during addiction behaviors

Thesis (Ph.D.)--University of Washington, 2016-08Addiction is a chronic neuropsychiatric disorder accompanied by high rates of recidivism that lacks effect treatment, part of which may be due to an incomplete understanding of the brain circuits mediating addiction. Cortico-basal ganglia circuitry is a complex, interconnected network regulating addiction. Aberrant glutamatergic signaling in NAc is particularly important for the development and persistent of addiction, and NAc neurons receive glutamatergic innervation from many structures, with prefrontal cortex (PFC) and midline and intralaminar thalamic nuclei (MTN) inputs predominating. Recently we developed a viral mediated gene transfer approach combined with chemogenetics that allows us to selectively activate Gi/o-signaling cascades to reduce neuronal activity in specifically prefrontal cortex (PFC) or MTN NAc afferents during addiction-related behaviors. Thus, the overall goal of this dissertation was to utilize these novel techniques to more clearly define the role of PFC or MTN neurons projecting to the NAc in the regulation of psychomotor sensitization, drug-self administration, and drug-seeking behaviors in rats. We found that reducing neuronal activity of PFC neurons projecting to NAc attenuated the development of amphetamine sensitization. However, attenuating activity of these neurons during sensitization enhanced conditioned responses during a subsequent challenge session. Furthermore, our corticostriatal manipulation did not alter drug-taking during self-administration, but led to slower rates of extinction and enhanced responding following a priming injection of cocaine. We normalized responding following inhibition of corticostriatal afferents immediately prior to the drug-primed reinstatement test. These results demonstrate that corticostriatal afferents modulate responsiveness to psychostimulant drugs and drug-associated stimuli. Considerably less is known about the relative contribution of MTN to relapse behaviors compared to other sources of NAc glutamate, despite sending dense projections to NAc. First, I demonstrate that reducing activity of MTN attenuates both cue-induced and drug-primed reinstatement of cocaine-seeking, which establishes a role of MTN in relapse behaviors. Then I show that dampening activity of specifically anterior MTN neurons projecting to NAc (MTN-NAc) abolished drug-prime reinstatement, but enhanced cue-induced reinstatement. We found no effect of the same manipulation in posterior MTN-NAc during either reinstatement behavior. These results demonstrate MTN mediate relapse behavior, and MTN-NAc may be particularly important for regulating responses to drug-associated stimuli

Acid-sensing ion channel-1a in the amygdala, a novel therapeutic target in depression-related behavior

No animal models replicate the complexity of human depression. However, a number of behavioral tests in rodents are sensitive to antidepressants and may thus tap important underlying biological factors. Such models may also offer the best opportunity to discover novel treatments. Here, we used several of these models to test the hypothesis that the acid-sensing ion channel-1a (ASIC1a) might be targeted to reduce depression. Genetically disrupting ASIC1a in mice produced antidepressant-like effects in the forced swim test, the tail suspension test, and following unpredictable mild stress. Pharmacologically inhibiting ASIC1a also had antidepressant-like effects in the forced swim test. The effects of ASIC1a disruption in the forced swim test were independent of and additive to those of several commonly used antidepressants. Furthermore, ASIC1a disruption interfered with an important biochemical marker of depression, the ability of stress to reduce BDNF in the hippocampus. Restoring ASIC1a to the amygdala of ASIC1a-/- mice with a viral vector reversed the forced swim test effects, suggesting that the amygdala is a key site of ASIC1a action in depression-related behavior. These data are consistent with clinical studies emphasizing the importance of the amygdala in mood regulation, and suggest that ASIC1a antagonists may effectively combat depression. Copyright © 2009 Society for Neuroscience