Neuronal glutamatergic synaptic clefts alkalinize rather than acidify during neurotransmission

URBANO FJ; UCHITEL OD

JOURNAL OF NEUROSCIENCE

SOC NEUROSCIENCE

Año: 2020 vol. 40 p. 1611 - 1624

0270-6474

Submitted on: (24 August 2020)Response to Stawarski et al (2020) and Niesman and Silva (2020 on Alkalization of Glutamatergic Synaptic CleftsOsvaldo D. Uchitel & Francisco J. Urbano. Instituto de Fisiología, Biología molecular y Neurociencias (IFIBYNE) UBA-CONICET, DFBMC. Facultad Cs. Exactas y Naturales, ARGENTINAWe would like to draw attention to the research article published in J. Neuroscience by Stawarski et al (2020) and commented in the Journal Club by Niesman & Silva (2020). In both publications, the synaptic currents dependent on the activation of the Acid Sensitive Ion Channels (ASIC) triggered by stimulation of the presynaptic terminal have not been discussed. In fact, presynaptic ASIC channels have been reported at amygdala, nucleus accumbens, calyx of Held and cingulate cortex (Du et al., 2014; Krepel et al, 2014, Gonzalez Inchauspe et al, 2017 and Li et al. 2019). To the best of our knowledge, ASIC channels can only be activated after a strong acidification of synaptic cleft (Grunder & Pusch, 2015).Our group have reported that ASIC1a-dependent synaptic currents elicited by vesicle release nerve-triggered stimulation of the calyx of Held were absent in ASIC1a−/− mice, and blocked by amiloride and by the specific ASIC1a channel blocker Psalmotoxin-1, thus confirming the involvement of ASIC-1a channels (Gonzalez-Inchauspe, 2017). Furthermore, ASIC-1a-dependent currents were inhibited by increasing the [H+] buffering capacity of the extracellular solution and were abolished when ASIC-1a were desensitized by a pH 6.0 extracellular solution. It is important to highlight that we?ve added MES during our experiments (pKa~6.2) in order to ensure extracellular [H+] buffering. Without proper buffer of extracellular [H+] an apparent alkalization might be underlined by an unbalanced acid-base equilibrium. Our results support the idea that synaptic released vesicle content acidifies the synaptic cleft and activates postsynaptic ASICs. Undoubtedly, the necessary acidification ought to be very transient. Furthermore, since high frequency stimulation of synapses at the anterior cingulate cortex induces an ASIC dependent LTP (Li et al 2019) it is possible to consider that even at high frequency stimulation a biphasic change in pH could occur at key points of the synaptic cleft not resolved with imaging methods used by Stawarski et al (2020).SincerelyOsvaldo D Uchitel & Francisco UrbanoDu, J., Reznikov, L. R., Price, M. P., Zha, X. M., Lu, Y., Moninger, T. O., Welsh, M. J. (2014). Protons are a neurotransmitter that regulates synaptic plasticity in the lateral amygdala. Proc Natl Acad Sci U S A, 111(24), 8961-8966. doi:10.1073/pnas.1407018111González-Inchauspe C, Urbano FJ, Di Guilmi MN, Uchitel OD. Acid-Sensing Ion Channels Activated by Evoked Released Protons Modulate Synaptic Transmission at the Mouse Calyx of Held Synapse. J Neurosci. 2017 Mar 8;37(10):2589-2599. doi: 10.1523/JNEUROSCI.2566-16.2017Grunder, S., & Pusch, M. (2015). Biophysical properties of acid-sensing ion channels (ASICs). Neuropharmacology, 94, 9-18. doi: 10.1016/j.neuropharm.2014.12.016Kreple, C. J., Lu, Y., Taugher, R. J., Schwager-Gutman, A. L., Du, J., Stump, M., . . . Wemmie, J. A. (2014). Acid-sensing ion channels contribute to synaptic transmission and inhibit cocaine-evoked plasticity. Nat Neurosci, 17(8), 1083-1091. doi:10.1038/nn.3750Li HS, Su XY, Song XL, Qi X, Li Y, Wang RQ, Maximyuk O, Krishtal O, Wang T, Fang H, Liao L, Cao H, Zhang YQ, Zhu MX, Liu MG, Xu TL.(2019) Protein kinase C lambda mediates acid-sensing ion channel 1a-dependent cortical synaptic plasticity and pain hypersensitivity. J Neurosci. 2019 May 17. pii: 0213-19. doi: 10.1523/JNEUROSCI.0213-19.2019.Niesman PJ, Silva V. Alkalinization of the Synaptic Cleft during Excitatory neurotransmission. J Neurosci. 2020 Aug 12;40(33):6267-6269. doi: 10.1523/JNEUROSCI.0914-20.2020.Stawarski M, Hernandez RX, Feghhi T, Borycz JA, Lu Z, Agarwal AB, Reihl KD, Tavora R, Lau AWC, Meinertzhagen IA, Renden R, Macleod GT. Neuronal Glutamatergic Synaptic Clefts Alkalinize Rather Than Acidify during Neurotransmission. J Neurosci. 2020 Feb 19;40(8):1611-1624. doi: 10.1523/JNEUROSCI.1774-19.2020.Competing Interests: None declared.