Skip to main content
SpringerLink
Log in

Aging is associated with a mild acidification in neocortical human neurons in vitro

  • Psychiatry and Preclinical Psychiatric Studies - Original Article
  • Published:
Journal of Neural Transmission Aims and scope Submit manuscript

Abstract

The intracellular pH (pHi) in the cytosol of mammalian central neurons is tightly regulated and small pHi-fluctuations are deemed to modulate inter-/intracellular signaling, excitability, and synaptic plasticity. The resting pHi of young rodent hippocampal pyramidal neurons is known to decrease alongside aging for about 0.1 pH-units. There is no information about the relationship between age and pHi of human central neurons. We addressed this knowledge gap using 26 neocortical slices from 12 patients (1–56-years-old) who had undergone epilepsy surgery. For fluorometric recordings, the slice-neurons were loaded with the pHi-sensitive dye BCECF-AM. We found that the pyramidal cells’ resting pHi (n = 26) descended linearly alongside aging (r = − 0.71, p < 0.001). This negative relationship persisted, when the sample was confined to specific brain regions (i.e., middle temporal gyrus, 23 neurons, r = − 0.68, p < 0.001) or pathologies (i.e., hippocampus sclerosis, 8 neurons, r = − 0.78, p = 0.02). Specifically, neurons (n = 9, pHi 7.25 ± 0.12) from young children (1.5 ± 0.46-years-old) were significantly more alkaline than neurons from adults (n = 17, 38.53 ± 12.38 years old, pHi 7.08 ± 0.07, p < 0.001). Although the samples were from patients with different pathologies the results were in line with those from the rodent hippocampal pyramidal neurons. Like a hormetin, the age-related mild pHi-decrease might contribute to neuroprotection, e.g., via limiting excitotoxicity. On the other hand, aging cortical neurons could become more vulnerable to metabolic overstress by a successive pHi-decrease. Certainly, its impact for the dynamics in short and long-term synaptic plasticity and, ultimately, learning and memory provides a challenge for further research.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

  • Aihara T, Kobayashi Y, Tsukada M (2005) Spatiotemporal visualization of long-term potentiation and depression in the hippocampal CA1 area. Hippocampus 15(1):68–78

    Article  PubMed  Google Scholar 

  • Baram TZ, Eghbal-Ahmadi M, Bender RA (2002) Is neuronal death required for seizure-induced epileptogenesis in the immature brain? Prog Brain Res 135:365–375

    Article  PubMed  PubMed Central  Google Scholar 

  • Bas-Orth C, Tan YW, Lau D, Bading H (2017) Synaptic activity drives a genomic program that promotes a neuronal warburg effect. J Biol Chem 292(13):5183–5194

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Berthet C, Lei H, Thevenet J, Gruetter R, Magistretti PJ, Hirt L (2009) Neuroprotective role of lactate after cerebral ischemia. J Cereb Blood Flow Metab 29:1780–1789

    Article  PubMed  CAS  Google Scholar 

  • Bonnet U, Wiemann M (2016) Verapamil and ethacrynic acid are associated with neuronal acidification in hippocampal CA3-neurons (slice preparation, guinea pig): Contribution to their anti-seizure potency? Pharmacol Res 110:50–51

    Article  PubMed  CAS  Google Scholar 

  • Bonnet U, Gastpar M, Bingmann D (1996) Ethacrynic acid: effects on postsynaptic GABA responses and electric activity of CA3 neurones. Neuroreport 7(18):2983–2987

    Article  PubMed  CAS  Google Scholar 

  • Bonnet U, Bingmann D, Wiemann M (2000) Intracellular pH modulates spontaneous and epileptiform bioelectric activity of hippocampal CA3-neurones. Eur Neuropsychopharmacol 10(2):97–103

    Article  PubMed  CAS  Google Scholar 

  • Bonnet U, Scherbaum N, Wiemann M (2008) The endogenous alkaloid harmane: acidifying and activity-reducing effects on hippocampal neurons in vitro. Prog Neuropsychopharmacol Biol Psychiatry 32(2):362–367

    Article  PubMed  CAS  Google Scholar 

  • Bonnet U, Bingmann D, Wiltfang J, Scherbaum N, Wiemann M (2010) Modulatory effects of neuropsychopharmaca on intracellular pH of hippocampal neurones in vitro. Br J Pharmacol 159(2):474–483

    Article  PubMed  CAS  Google Scholar 

  • Boyarsky G, Hanssen C, Clyne LA (1996) Superiority of in vitro over in vivo calibrations of BCECF in vascular smooth muscle cells. FASEB J 10:1205–1212

    Article  PubMed  CAS  Google Scholar 

  • Bozzo L, Puyal J, Chatton JY (2013) Lactate modulates the activity of primary cortical neurons through a receptor-mediated pathway. PLoS One 8:e71721

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Chesler M (2003) Regulation and modulation of pH in the brain. Physiol Rev 83(4):1183–1221

    Article  PubMed  CAS  Google Scholar 

  • Diering GH, Numata M (2014) Endosomal pH in neuronal signaling and synaptic transmission: role of Na(+)/H(+) exchanger NHE5. Front Physiol 4:412

    Article  PubMed  PubMed Central  Google Scholar 

  • Dulla CG, Frenguelli BG, Staley KJ, Masino SA (2009) Intracellular acidification causes adenosine release during states of hyperexcitability in the hippocampus. J Neurophysiol 102:1984–1993

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Farsi Z, Jahn R, Woehler A A (2017) Proton electrochemical gradient: driving and regulating neurotransmitter uptake. Bioessays 39(5):1600240

    Article  CAS  Google Scholar 

  • Graebenitz S, Cerina M, Lesting J, Kedo O, Gorji A, Pannek H, Hans V, Zilles K, Pape H-C, Speckmann EJ (2017) Directional spread of activity in synaptic networks of the human lateral amygdala. Neuroscience 349:330–340

    Article  PubMed  CAS  Google Scholar 

  • Hong YT, Veenith T, Dewar D, Outtrim JG, Mani V, Williams C, Pimlott S, Hutchinson PJ, Tavares A, Canales R, Mathis CA, Klunk WE, Aigbirhio FI, Coles JP, Baron JC, Pickard JD, Fryer TD, Stewart W, Menon DK (2014) Amyloid imaging with carbon 11-labeled Pittsburgh compound B for traumatic brain injury. JAMA Neurol 71(1):23–31

    Article  PubMed  PubMed Central  Google Scholar 

  • Jedlicka P, Deller T, Gutkin BS, Backus KH (2011) Activity-dependent intracellular chloride accumulation and diffusion controls GABA(A) receptor-mediated synaptic transmission. Hippocampus 21(8):885–898

    PubMed  CAS  Google Scholar 

  • Kaila K, Ruusuvuori E, Seja V, Voipio J, Puskarov M (2014) GABA actions and ionic plasticity in epilepsy. Curr Opin Neurobiol 26:34–41

    Article  PubMed  CAS  Google Scholar 

  • Köhling R, Lücke A, Straub H, Speckmann E-J (1996) A portable chamber for long-distance transport of surviving human brain slice preparations. J Neurosci Methods 67:233–236

    Article  PubMed  Google Scholar 

  • Lam TI, Brennan-Minnella AM, Won SJ, Shen Y, Hefner C, Shi Y, Sun D, Swanson RA (2013) Intracellular pH reduction prevents excitotoxic and ischemic neuronal death by inhibiting NADPH oxidase. Proc Natl Acad Sci USA 110:E4362–E4368

    Article  PubMed  CAS  Google Scholar 

  • Lee BK, Jung YS (2017) Sustained intracellular acidosis triggers the Na+/H+ exchager-1 activation in glutamate excitotoxicity. Biomol Ther (Seoul) 25(6):593–598

    Article  Google Scholar 

  • Magnotta VA, Heo HY, Dlouhy BJ, Dahdaleh NS, Follmer RL, Thedens DR, Welsh MJ, Wemmie JA (2012) Detecting activity-evoked pH changes in human brain. Proc Natl Acad Sci USA 109(21):8270–8273

    Article  PubMed  Google Scholar 

  • Mohapatra N, Tønnesen J, Vlachos A, Kuner T, Deller T, Nägerl UV, Santamaria F, Jedlicka P (2016) Spines slow down dendritic chloride diffusion and affect short-term ionic plasticity of GABAergic inhibition. Sci Rep 6:23196

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Nixon RA (2017) Amyloid precursor protein and endosomal-lysosomal dysfunction in Alzheimer’s disease: inseparable partners in a multifactorial disease. FASEB J 31(7):2729–2743

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Obara M, Szeliga M, Albrecht J (2008) Regulation of pH in the mammalian central nervous system under normal and pathological conditions: facts and hypotheses. Neurochem Int 52(6):905–919

    Article  PubMed  CAS  Google Scholar 

  • Prasad H, Rao R (2015) The Na+/H+ exchanger NHE6 modulates endosomal pH to control processing of amyloid precursor protein in a cell culture model of Alzheimer disease. J Biol Chem 290(9):5311–5327

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Puskarjov M, Kahle KT, Ruusuvuori E, Kaila K (2014) Pharmacotherapeutic targeting of cation-chloride cotransporters in neonatal seizures. Epilepsia 55(6):806–818

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Raimondo JV, Markram H, Akerman CJ (2012) Short-term ionic plasticity at GABAergic synapses. Front Synaptic Neurosci 4:5

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Rattan SI (2008) Hormesis in aging. Ageing Res Rev 7(1):63–78

    Article  PubMed  Google Scholar 

  • Roberts EL, Chih CP (1998) The pH buffering capacity of hippocampal slices from young adult and aged rats. Brain Res 779:271–275

    Article  PubMed  CAS  Google Scholar 

  • Roberts EL, Sick TJ (1996) Aging impairs regulation of intracellular pH in rat hippocampal slices. Brain Res 735(2):339–342

    Article  PubMed  CAS  Google Scholar 

  • Ruffin VA, Salameh AI, Boron WF, Parker MD (2014) Intracellular pH regulation by acid-base transporters in mammalian neurons. Front Physiol 5:43

    Article  PubMed  PubMed Central  Google Scholar 

  • Ruusuvuori E, Kaila K (2014) Carbonic anhydrases and brain pH in the control of neuronal excitability. Subcell Biochem 75:271–290

    Article  PubMed  CAS  Google Scholar 

  • Ruusuvuori E, Kirilkin I, Pandya N, Kaila K (2010) Spontaneous network events driven by depolarizing GABA action in neonatal hippocampal slices are not attributable to deficient mitochondrial energy metabolism. J Neurosci 30:15638–15642

    Article  PubMed  CAS  Google Scholar 

  • Seranova E, Connolly KJ, Zatyka M, Rosenstock TR, Barrett T, Tuxworth RI, Sarkar S (2017) Dysregulation of autophagy as a common mechanism in lysosomal storage diseases. Essays Biochem 61(6):733–749

    Article  PubMed  PubMed Central  Google Scholar 

  • Sinning A, Hübner CA (2013) Minireview: pH and synaptic transmission. FEBS Lett 587(13):1923–1928

    Article  PubMed  CAS  Google Scholar 

  • Straub H, Kuhnt U, Höhling JM, Köhling R, Gorji A, Kuhlmann D, Tuxhorn I, Ebner A, Wolf P, Pannek HW, Lahl R, Speckmann E-J (2003) Stimulus-induced patterns of bioelectric activity in human neocortical tissue recorded by a voltage sensitive dye. Neuroscience 121(3):587–604

    Article  PubMed  CAS  Google Scholar 

  • Sulis Sato S, Artoni P, Landi S, Cozzolino O, Parra R, Pracucci E, Trovato F, Szczurkowska J, Luin S, Arosio D, Beltram F, Cancedda L, Kaila K, Ratto GM (2017) Simultaneous two-photon imaging of intracellular chloride concentration and pH in mouse pyramidal neurons in vivo. Proc Natl Acad Sci USA 114(41):E8770–E8779

    Article  PubMed  CAS  Google Scholar 

  • Sun MK, Alkon DL (2002) Carbonic anhydrase gating of attention: memory therapy and enhancement. Trends Pharmacol Sci 23(2):83–89

    Article  PubMed  CAS  Google Scholar 

  • Tantama M, Hung YP, Yellen G (2011) Imaging intracellular pH in live cells with a genetically encoded red fluorescent protein sensor. J Am Chem Soc 133(26):10034–10037

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Tyrtyshnaia AA, Lysenko LV, Madamba F, Manzhulo IV, Khotimchenko MY, Kleschevnikov AM (2016) Acute neuroinflammation provokes intracellular acidification in mouse hippocampus. J Neuroinflamm 13(1):283

    Article  CAS  Google Scholar 

  • Vingtdeux V, Hamdane M, Bégard S, Loyens A, Delacourte A, Beauvillain JC, Buée L, Marambaud P, Sergeant N (2007) Intracellular pH regulates amyloid precursor protein intracellular domain accumulation. Neurobiol Dis 25(3):686–696

    Article  PubMed  CAS  Google Scholar 

  • Vlachos A (2012) Synaptopodin and the spine apparatus organelle-regulators of different forms of synaptic plasticity? Ann Anat 194(4):317–320

    Article  PubMed  CAS  Google Scholar 

  • Wiemann M, Splettstoesser F, Pannek HW, Behne F, Speckmann EJ, Bingmann D (2006) Effects of levetiracetam and topiramate on pHi regulation of human neocortical brain slices. Acta Physiol 186:126 (Supplement 650; PM03P-6)

    Google Scholar 

  • Xiang Z, Bergold PJ (2000) Synaptic depression and neuronal loss in transiently acidic hippocampal slice cultures. Brain Res 881:77–87

    Article  PubMed  CAS  Google Scholar 

  • Xiong ZQ, Saggau P, Stringer JL (2000) Activity-dependent intracellular acidification correlates with the duration of seizure activity. J Neurosci 20:1290–1296

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgements

We cordially thank Dr. med. F. Behne and Dr. med. H. Pannek (Department of Neurosurgery of the Evangelisches Krankenhaus Bielefeld) for supplying the study material to us.

Funding

None.

Author information

Authors and Affiliations

  1. Department of Psychiatry, Psychotherapy, and Psychosomatic Medicine, Evangelisches Krankenhaus Castrop-Rauxel, Academic Teaching Hospital of the University Duisburg-Essen, Castrop-Rauxel, Germany

    Udo Bonnet

  2. Department of Psychiatry and Psychotherapy, Faculty of Medicine, LVR-Hospital Essen, University of Duisburg-Essen, Essen, Germany

    Udo Bonnet

  3. Institute of Physiology, University of Duisburg-Essen, Essen, Germany

    Dieter Bingmann & Martin Wiemann

  4. Institute of Physiology, University of Münster, Münster, Germany

    Erwin-Josef Speckmann

  5. IBE R&D gGmbH, Institute for Lung Health, 48149, Münster, Germany

    Martin Wiemann

Authors
  1. Udo Bonnet
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Dieter Bingmann
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Erwin-Josef Speckmann
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Martin Wiemann
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Conception: MW, UB; collection of the data: MW; analysis and interpretation of data: MW, UB, DB, E-JS; drafting the article: UB, revising it critically for important intellectual content: DB, E-JS.

Corresponding author

Correspondence to Udo Bonnet.

Ethics declarations

Conflict of interest

U.B., D.B. and M.W. contributed to a patent hold by Marion Roussel, Germany: “Use of an inhibitor of the Na+/H+ exchanger for the production of a medicament for the treatment or prophylaxis of disturbances of the central nervous system”. Publication Date: April 28, 2003. Application number: 10424107, http://patents.justia.com/patent/20040097544 (assessed at 06/16/2018). E.-J.S has none to declare.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Bonnet, U., Bingmann, D., Speckmann, EJ. et al. Aging is associated with a mild acidification in neocortical human neurons in vitro. J Neural Transm 125, 1495–1501 (2018). https://doi.org/10.1007/s00702-018-1904-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00702-018-1904-2

Keywords

Search

Navigation