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Acid-sensing ion channels contribute to synaptic transmission and inhibit cocaine-evoked plasticity

Nature Neuroscience volume 17, pages 1083–1091 (2014)Cite this article

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Abstract

Acid-sensing ion channel 1A (ASIC1A) is abundant in the nucleus accumbens (NAc), a region known for its role in addiction. Because ASIC1A has been suggested to promote associative learning, we hypothesized that disrupting ASIC1A in the NAc would reduce drug-associated learning and memory. However, contrary to this hypothesis, we found that disrupting ASIC1A in the mouse NAc increased cocaine-conditioned place preference, suggesting an unexpected role for ASIC1A in addiction-related behavior. Moreover, overexpressing ASIC1A in rat NAc reduced cocaine self-administration. Investigating the underlying mechanisms, we identified a previously unknown postsynaptic current during neurotransmission that was mediated by ASIC1A and ASIC2 and thus well positioned to regulate synapse structure and function. Consistent with this possibility, disrupting ASIC1A altered dendritic spine density and glutamate receptor function, and increased cocaine-evoked plasticity, which resemble changes previously associated with cocaine-induced behavior. Together, these data suggest that ASIC1A inhibits the plasticity underlying addiction-related behavior and raise the possibility of developing therapies for drug addiction by targeting ASIC-dependent neurotransmission.

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Figure 1: ASIC1A is necessary for acid-evoked currents in the NAc and disrupting ASIC1A increases conditioned place preference to cocaine and morphine.
Figure 2: Restoring ASIC1A in the NAc re-establishes acid-evoked currents and reduces cocaine conditioned place preference.
Figure 3: ASIC1A and ASIC2 contribute to synaptic currents in NAc.
Figure 4: Reducing buffering capacity and inhibiting or deleting CA-IV increased ASIC EPSC in NAc.
Figure 5: Loss of ASIC1A increases dendritic spine density and mEPSC frequency in the NAc.
Figure 6: Loss of ASIC1A increases inward rectification of AMPA-mediated EPSCs, which is normalized by re-establishing ASIC1A expression in the NAc.
Figure 7: ASIC1A disruption increases the AMPA-to-NMDA ratio in NAc, which is acutely reversed by single cocaine dose.
Figure 8: Overexpressing ASIC1A in the rat NAc attenuates cocaine self-administration.

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Acknowledgements

We thank M. Lutter and M. Price for critically reading the manuscript. We also thank M. Price for providing Asic2−/− mice. We thank the University of Iowa Gene Transfer Vector Core and Central Microscopy Research Facility. J.A.W. was supported by the Department of Veterans Affairs (Merit Award), the National Institute of Mental Health (5R01MH085724), the US National Institutes of Health Heart, Lung, and Blood Institute (R01HL113863) and a NARSAD Independent Investigator Award. J.J.R. was supported by the US National Institutes of Health (MH095972). R.T.L. was supported by the US National Institutes of Health (DA034684). C.J.K. was supported by the University of Iowa Interdisciplinary Training Program in Pain Research National Institute of Neurological Disorders and Stroke T32NS045549. M.J.W. receives funding from the Howard Hughes Medical Institute.

Author information

Author notes

  1. Collin J Kreple and Yuan Lu: These authors contributed equally to this work.

Authors and Affiliations

  1. Medical Scientist Training Program, University of Iowa, Iowa City, Iowa, USA

    Collin J Kreple & Madeliene Stump

  2. Department of Molecular Physiology and Biophysics, University of Iowa, Iowa City, Iowa, USA

    Collin J Kreple, Michael J Welsh & John A Wemmie

  3. Department of Psychiatry, University of Iowa, Iowa City, Iowa, USA

    Yuan Lu, Yimo Wang, Ali Ghobbeh, Rong Fan & John A Wemmie

  4. Interdisciplinary Graduate Program in Neuroscience, University of Iowa, Iowa City, Iowa, USA

    Rebecca J Taugher, Madeliene Stump, Michael J Welsh, Jason J Radley, Ryan T LaLumiere & John A Wemmie

  5. Department of Psychology, University of Iowa, Iowa City, Iowa, USA

    Andrea L Schwager-Gutman, Caitlin V Cosme, Michael J Welsh, Jason J Radley & Ryan T LaLumiere

  6. Department of Internal Medicine, University of Iowa, Iowa City, Iowa, USA

    Jianyang Du

  7. Department of Neurology, University of Iowa, Iowa City, Iowa, USA

    Levi P Sowers

  8. Department of Neurosurgery, University of Iowa, Iowa City, Iowa, USA

    Michael J Welsh & John A Wemmie

  9. Howard Hughes Medical Institute, Iowa City, Iowa, USA

    Michael J Welsh

  10. Department of Veterans Affairs Medical Center, Iowa City, Iowa, USA

    John A Wemmie

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Contributions

All of the authors read and critiqued the manuscript. C.J.K., Y.L., R.J.T., A.L.S.-G., M.S., Y.W., A.G., R.F., C.V.C., L.P.S. and J.J.R. performed the experiments. C.J.K., Y.L., J.D., M.J.W., J.J.R., R.T.L. and J.A.W. designed the experiments. C.J.K., Y.L., R.T.L. and J.A.W. wrote the manuscript. R.T.L. and J.A.W. provided funding for the experiments.

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Correspondence to John A Wemmie.

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Integrated supplementary information

Supplementary Figure 1 Injection of AAV-Cre into the NAc reduces ASIC1A protein expression and acid-evoked currents.

(a) All protein used for the blot was obtained from the nucleus accumbens or COS cells. ASIC1A (in red) is present in COS cells, Asic1a+/+ mice, Asic1aloxP/loxP mice after AAV-eGFP delivery. ASIC1A labeling is diminished in Asic1aloxP/loxP mice after AAV-Cre delivery, and absent in Asic1a−/− mice. GAPDH (in green) was used as a loading control. (b) Delivery of AAV-Cre into the NAc of Asic1aloxP/loxP mice nearly abolishes acid-evoked currents (***p<0.001, Student's t test with Welch's correction, n=7-10 neurons).

Supplementary Figure 2 Restoring ASIC1A in the dorsal hippocampus does not reduce cocaine CPP.

In contrast to expressing ASIC1A in the NAc, restoring ASIC1A expression to the dorsal hippocampus of Asic1a−/−mice with AAV-Asic1a does not reduce conditioned place preference to cocaine (10 mg/kg) (p = 0.15, Student;s t test, n=7-9).

Supplementary Figure 3 Cocaine administration does not alter pH in the NAc, as measured by fiberoptic pH sensor in anesthetized mice.

Image shows continuous pH recording in the NAc during 20% CO2 inhalation and cocaine injection (10 mg/kg). 20% CO2 caused a robust acidosis, while cocaine administration did not alter pH.

Supplementary Figure 4 Amiloride inhibits evoked EPSCs in wild-type and Asic1a−/− mice.

(a) Representative traces of EPSCs before (black) and after (red) addition of amiloride to the slice bath. (b) Quantification of residual EPSC after amiloride application, normalized to the unblocked EPSC peak. A two-way ANOVA reveals a significant effect of amiloride (F(1, 24) = 199, p<0.001, n=5-8 neurons), but no significant effect of genotype (F(1, 24) = 0.2369, p>0.05, n=5-8 neurons), and no amiloride by genotype interaction (F(1, 24) = 0.2568, p>0.05, n=5-8 neurons). Planned post-hoc tests reveal a significant reduction in the peak EPSC amplitude after amiloride treatment in Asic1a+/+ (***p<0.001) and Asic1a−/− mice (***p<0.001, Sidak's multiple comparisons test).

Supplementary Figure 5 The relationship between the total evoked EPSC and the residual evoked EPSC in the presence of AP5, CNQX and picrotoxin.

The relative proportion of the residual amiloride sensitive synaptic current does not change with changes in amplitude of evoked EPSCs. The red line illustrates the linear fit of the result: y = 0.0004x + 5.1315, r2 = 0.0465.

Supplementary Figure 6 Loss of ASIC1A does not change mEPSC amplitude in the NAc.

(a) Cumulative fraction of mEPSC amplitude, and histogram of mEPSC amplitude (inset) in Asic1a+/+ and Asic1a−/− mice. (b) Cumulative fraction of mEPSC amplitude, and histogram of mEPSC amplitude (inset) in Asic1a−/− mice injected with AAV-Asic1a or AAV-eGFP. (c) mEPSC amplitude is unchanged in Asic1a−/− mice or Asic1a−/− mice injected with AAV-Asic1a. A one-way ANOVA revealed no significant differences between groups (F(3, 56) = 1.359, p>0.05, n=11-18 neurons).

Supplementary Figure 7 Loss of ASIC1A does not alter paired pulse facilitation (PPF) in the NAc.

(a) Sample traces showing PPF in the NAc of Asic1a+/+ and Asic1a−/− mice. (b) Loss of ASIC1A does not alter PPF in the NAc (Student's t-test, p>0.05, n=9 neurons)

Supplementary Figure 8 Loss of ASIC1A does not alter body weight.

Body weight does not differ significantly between Asic1a+/+ and Asic1a−/− mice. A two-way ANOVA revealed a significant effect of sex (F(1, 122)= 192.7, p<0.001), but not genotype (F(1, 122)= 0.1084, p>0.05). Additionally, there was no significant sex by genotype interaction (F(1, 122)= 2.536, p>0.05).

Supplementary Figure 9 A diagram illustrating production strategy of our Asic1aloxP/loxP mice.

The top allele represents the portion of Asic1a encompassing exons 1, 2, and 3. The targeting vector, labeled “Recombinant” was obtained through standard molecular cloning and contained loxP sites flanking exon 2 and a neomycin resistance cassette. The neomycin resistance cassette was flanked by FRT and removed at the embryonic stem cell stage by flippase transfection. The resulting allele contains exon 2 flanked by loxP sites, allowing for specific deletion using Cre recombinase.

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Kreple, C., Lu, Y., Taugher, R. et al. Acid-sensing ion channels contribute to synaptic transmission and inhibit cocaine-evoked plasticity. Nat Neurosci 17, 1083–1091 (2014). https://doi.org/10.1038/nn.3750

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