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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Molecular mechanism and structural basis of small-molecule modulation of the gating of acid-sensing ion channel 1
Communications Biology Open Access 09 February 2021
Neuroscience Bulletin Open Access 30 September 2020
Molecular Brain Open Access 29 September 2020
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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.
The authors declare no competing financial interests.
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).
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.
(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.
(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).
(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)
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).
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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