Firing properties of entorhinal cortex neurons and early alterations in an Alzheimer's disease transgenic model

  • Andrea Marcantoni
  • Elisabeth F. Raymond
  • Emilio Carbone
  • Hélène Marie


The entorhinal cortex (EC) is divided into medial (MEC) and lateral (LEC) anatomical areas, and layer II neurons of these two regions project to granule cells of the dentate gyrus through the medial and lateral perforant pathways (MPP and LPP), respectively. Stellate cells (SCs) represent the main neurons constituting the MPP inputs, while fan cells (FCs) represent the main LPP inputs. Here, we first characterized the excitability properties of SCs and FCs in adult wild-type (WT) mouse brain. Our data indicate that, during sustained depolarization, action potentials (APs) generated by SCs exhibit increased fast afterhyperpolarization and overshoot, making them able to fire at higher frequencies and to exhibit higher spike frequency adaptation (SFA) than FCs. Since the EC is one of the earliest brain regions affected during Alzheimer's disease (AD) progression, we compared SCs and FCs firing in 4-month-old WT and transgenic Tg2576 mice, a well-established AD mouse model. Tg2576-SCs displayed a slight increase in firing frequency during mild depolarization but otherwise normal excitability properties during higher stimulations. On the contrary, Tg2576-FCs exhibited a decreased firing frequency during mild and higher depolarizations, as well as an increased SFA. Our data identify the FCs as a neuronal population particularly sensitive to early pathological effects of chronic accumulation of APP-derived peptides, as it occurs in Tg2576 mice. As FCs represent the major input of sensory information to the hippocampus during memory acquisition, early alterations in their excitability profile could significantly contribute to the onset of cognitive decline in AD.


Action potentials Stellate cells Fan cells Alzheimer's disease Tg2576 mice 



This work was financed by the ATIP/AVENIR program (Centre National de la RechercheScientifique, CNRS) to HM, by the French Fondation pour la Coopération Scientifique—Plan Alzheimer 2008–2012 (Senior Innovative Grant 2010) to HM, by the EFR to AM and by the Euro-Mediterranean PRES project (2013) to AM.


  1. 1.
    Alonso A, Klink R (1993) Differential electroresponsiveness of stellate and pyramidal-like cells of medial entorhinal cortex layer II. J Neurophysiol 70:128–143PubMedGoogle Scholar
  2. 2.
    Bean BP (2007) The action potential in mammalian central neurons. Nat Rev Neurosci 8:451–465PubMedCrossRefGoogle Scholar
  3. 3.
    Benda J, Herz AV (2003) A universal model for spike-frequency adaptation. Neural Comput 15:2523–2564PubMedCrossRefGoogle Scholar
  4. 4.
    Braak H, Braak E (1991) Neuropathological stageing of Alzheimer-related changes. Acta Neuropathol 82:239–259PubMedCrossRefGoogle Scholar
  5. 5.
    Canto CB, Witter MP (2012) Cellular properties of principal neurons in the rat entorhinal cortex. I. The lateral entorhinal cortex. Hippocampus 22:1256–1276PubMedCrossRefGoogle Scholar
  6. 6.
    Canto CB, Witter MP (2012) Cellular properties of principal neurons in the rat entorhinal cortex. II. The medial entorhinal cortex. Hippocampus 22:1277–1299PubMedCrossRefGoogle Scholar
  7. 7.
    Canto CB, Wouterlood FG, Witter MP (2008) What does the anatomical organization of the entorhinal cortex tell us? Neural Plast 2008:381243PubMedCentralPubMedCrossRefGoogle Scholar
  8. 8.
    Carbone E, Lux HD (1987) Kinetics and selectivity of a low-voltage-activated calcium current in chick and rat sensory neurones. J Physiol 386:547–570PubMedCentralPubMedGoogle Scholar
  9. 9.
    Colbert CM, Magee JC, Hoffman DA, Johnston D (1997) Slow recovery from inactivation of Na+ channels underlies the activity-dependent attenuation of dendritic action potentials in hippocampal CA1 pyramidal neurons. J Neurosci 17:6512–6521PubMedGoogle Scholar
  10. 10.
    D'Amelio M, Cavallucci V, Middei S, Marchetti C, Pacioni S, Ferri A, Diamantini A, De ZD, Carrara P, Battistini L, Moreno S, Bacci A, Ammassari-Teule M, Marie H, Cecconi F (2011) Caspase-3 triggers early synaptic dysfunction in a mouse model of Alzheimer's disease. Nat Neurosci 14:69–76PubMedCrossRefGoogle Scholar
  11. 11.
    Dickson CT, Magistretti J, Shalinsky MH, Fransen E, Hasselmo ME, Alonso A (2000) Properties and role of I(h) in the pacing of subthreshold oscillations in entorhinal cortex layer II neurons. J Neurophysiol 83:2562–2579PubMedGoogle Scholar
  12. 12.
    Dong H, Martin MV, Chambers S, Csernansky JG (2007) Spatial relationship between synapse loss and beta-amyloid deposition in Tg2576 mice. J Comp Neurol 500:311–321PubMedCentralPubMedCrossRefGoogle Scholar
  13. 13.
    Eichenbaum H, Yonelinas AP, Ranganath C (2007) The medial temporal lobe and recognition memory. Annu Rev Neurosci 30:123–152PubMedCentralPubMedCrossRefGoogle Scholar
  14. 14.
    Fuhrmann G, Markram H, Tsodyks M (2002) Spike frequency adaptation and neocortical rhythms. J Neurophysiol 88:761–770PubMedGoogle Scholar
  15. 15.
    Garden DL, Dodson PD, O'Donnell C, White MD, Nolan MF (2008) Tuning of synaptic integration in the medial entorhinal cortex to the organization of grid cell firing fields. Neuron 60:875–889PubMedCrossRefGoogle Scholar
  16. 16.
    Gettes LS, Reuter H (1974) Slow recovery from inactivation of inward currents in mammalian myocardial fibres. J Physiol 240:703–724PubMedCentralPubMedGoogle Scholar
  17. 17.
    Gomez-Isla T, Price JL, McKeel DW Jr, Morris JC, Growdon JH, Hyman BT (1996) Profound loss of layer II entorhinal cortex neurons occurs in very mild Alzheimer's disease. J Neurosci 16:4491–4500PubMedGoogle Scholar
  18. 18.
    Heys JG, Hasselmo ME (2012) Neuromodulation of I(h) in layer II medial entorhinal cortex stellate cells: a voltage-clamp study. J Neurosci 32:9066–9072PubMedCentralPubMedCrossRefGoogle Scholar
  19. 19.
    Hsiao K, Chapman P, Nilsen S, Eckman C, Harigaya Y, Younkin S, Yang F, Cole G (1996) Correlative memory deficits, Abeta elevation, and amyloid plaques in transgenic mice. Science 274:99–102PubMedCrossRefGoogle Scholar
  20. 20.
    Jenerick H (1963) Phase plane trajectories of the muscle spike potential. Biophys J 3:363–377PubMedCentralPubMedCrossRefGoogle Scholar
  21. 21.
    Jones RS (1993) Entorhinal–hippocampal connections: a speculative view of their function. Trends Neurosci 16:58–64PubMedCrossRefGoogle Scholar
  22. 22.
    Khaliq ZM, Bean BP (2010) Pacemaking in dopaminergic ventral tegmental area neurons: depolarizing drive from background and voltage-dependent sodium conductances. J Neurosci 30:7401–7413PubMedCentralPubMedCrossRefGoogle Scholar
  23. 23.
    Khawaja FA, Alonso AA, Bourque CW (2007) Ca(2+)-dependent K(+) currents and spike-frequency adaptation in medial entorhinal cortex layer II stellate cells. Hippocampus 17:1143–1148PubMedCrossRefGoogle Scholar
  24. 24.
    Klink R, Alonso A (1993) Ionic mechanisms for the subthreshold oscillations and differential electroresponsiveness of medial entorhinal cortex layer II neurons. J Neurophysiol 70:144–157PubMedGoogle Scholar
  25. 25.
    Klink R, Alonso A (1997) Morphological characteristics of layer II projection neurons in the rat medial entorhinal cortex. Hippocampus 7:571–583PubMedCrossRefGoogle Scholar
  26. 26.
    Kovacs T, Cairns NJ, Lantos PL (2001) Olfactory centres in Alzheimer's disease: olfactory bulb is involved in early Braak's stages. Neuroreport 12:285–288PubMedCrossRefGoogle Scholar
  27. 27.
    Ladenbauer J, Augustin M, Shiau L, Obermayer K (2012) Impact of adaptation currents on synchronization of coupled exponential integrate-and-fire neurons. PLoS Comput Biol 8:e1002478PubMedCentralPubMedCrossRefGoogle Scholar
  28. 28.
    Leutgeb JK, Frey JU, Behnisch T (2003) LTP in cultured hippocampal–entorhinal cortex slices from young adult (P25-30) rats. J Neurosci Methods 130:19–32PubMedCrossRefGoogle Scholar
  29. 29.
    Madison DV, Nicoll RA (1984) Control of the repetitive discharge of rat CA 1 pyramidal neurones in vitro. J Physiol 354:319–331PubMedCentralPubMedGoogle Scholar
  30. 30.
    Marchetti C, Marie H (2011) Hippocampal synaptic plasticity in Alzheimer's disease: what have we learned so far from transgenic models? Rev Neurosci 22:373–402PubMedCrossRefGoogle Scholar
  31. 31.
    Masdeu JC, Zubieta JL, Arbizu J (2005) Neuroimaging as a marker of the onset and progression of Alzheimer's disease. J Neurol Sci 236:55–64PubMedCrossRefGoogle Scholar
  32. 32.
    Mayeaux DJ, Johnston RE (2004) Discrimination of social odors and their locations: role of lateral entorhinal area. Physiol Behav 82:653–662PubMedCrossRefGoogle Scholar
  33. 33.
    Palop JJ, Mucke L (2010) Amyloid-beta-induced neuronal dysfunction in Alzheimer's disease: from synapses toward neural networks. Nat Neurosci 13:812–818PubMedCentralPubMedCrossRefGoogle Scholar
  34. 34.
    Pastoll H, Ramsden HL, Nolan MF (2012) Intrinsic electrophysiological properties of entorhinal cortex stellate cells and their contribution to grid cell firing fields. Front Neural Circ 6:17Google Scholar
  35. 35.
    Ripoli C, Piacentini R, Riccardi E, Leone L, Li Puma DD, Bitan G, Grassi C (2013) Effects of different amyloid beta-protein analogues on synaptic function. Neurobiol Aging 34:1032–1044PubMedCrossRefGoogle Scholar
  36. 36.
    Sah P (1996) Ca(2+)-activated K + currents in neurones: types, physiological roles and modulation. Trends Neurosci 19:150–154PubMedCrossRefGoogle Scholar
  37. 37.
    Schultz H, Sommer T, Peters J (2012) Direct evidence for domain-sensitive functional subregions in human entorhinal cortex. J Neurosci 32:4716–4723PubMedCrossRefGoogle Scholar
  38. 38.
    Selkoe DJ (2002) Alzheimer's disease is a synaptic failure. Science 298:789–791PubMedCrossRefGoogle Scholar
  39. 39.
    Shay CF, Boardman IS, James NM, Hasselmo ME (2012) Voltage dependence of subthreshold resonance frequency in layer II of medial entorhinal cortex. Hippocampus 22:1733–1749PubMedCentralPubMedCrossRefGoogle Scholar
  40. 40.
    Sohrabi HR, Bates KA, Weinborn MG, Johnston AN, Bahramian A, Taddei K, Laws SM, Rodrigues M, Morici M, Howard M, Martins G, Mackay-Sim A, Gandy SE, Martins RN (2012) Olfactory discrimination predicts cognitive decline among community-dwelling older adults. Transl Psychiatry 2:e118PubMedCentralPubMedCrossRefGoogle Scholar
  41. 41.
    Solomon JS, Nerbonne JM (1993) Two kinetically distinct components of hyperpolarization-activated current in rat superior colliculus-projecting neurons. J Physiol 469:291–313PubMedCentralPubMedGoogle Scholar
  42. 42.
    Sperling RA, Dickerson BC, Pihlajamaki M, Vannini P, LaViolette PS, Vitolo OV, Hedden T, Becker JA, Rentz DM, Selkoe DJ, Johnson KA (2010) Functional alterations in memory networks in early Alzheimer's disease. Neuromol Med 12:27–43CrossRefGoogle Scholar
  43. 43.
    Storm JF (1987) Action potential repolarization and a fast after-hyperpolarization in rat hippocampal pyramidal cells. J Physiol 385:733–759PubMedCentralPubMedGoogle Scholar
  44. 44.
    Stranahan AM, Mattson MP (2010) Selective vulnerability of neurons in layer II of the entorhinal cortex during aging and Alzheimer's disease. Neural Plast 2010:108190PubMedCentralPubMedCrossRefGoogle Scholar
  45. 45.
    Tahvildari B, Alonso A (2005) Morphological and electrophysiological properties of lateral entorhinal cortex layers II and III principal neurons. J Comp Neurol 491:123–140PubMedCrossRefGoogle Scholar
  46. 46.
    Takeuchi A, Irizarry MC, Duff K, Saido TC, Hsiao AK, Hasegawa M, Mann DM, Hyman BT, Iwatsubo T (2000) Age-related amyloid beta deposition in transgenic mice overexpressing both Alzheimer mutant presenilin 1 and amyloid beta precursor protein Swedish mutant is not associated with global neuronal loss. Am J Pathol 157:331–339PubMedCentralPubMedCrossRefGoogle Scholar
  47. 47.
    Thal DR, Rub U, Orantes M, Braak H (2002) Phases of A beta-deposition in the human brain and its relevance for the development of AD. Neurology 58:1791–1800PubMedCrossRefGoogle Scholar
  48. 48.
    Van Hoesen GW, Augustinack JC, Dierking J, Redman SJ, Thangavel R (2000) The parahippocampal gyrus in Alzheimer's disease. Clinical and preclinical neuroanatomical correlates. Ann N Y Acad Sci 911:254–274PubMedCrossRefGoogle Scholar
  49. 49.
    van Strien NM, Cappaert NL, Witter MP (2009) The anatomy of memory: an interactive overview of the parahippocampal–hippocampal network. Nat Rev Neurosci 10:272–282PubMedCrossRefGoogle Scholar
  50. 50.
    Vandael DH, Zuccotti A, Striessnig J, Carbone E (2012) Ca(V)1.3-driven SK channel activation regulates pacemaking and spike frequency adaptation in mouse chromaffin cells. J Neurosci 32:16345–16359PubMedCrossRefGoogle Scholar
  51. 51.
    Verret L, Jankowsky JL, Xu GM, Borchelt DR, Rampon C (2007) Alzheimer's-type amyloidosis in transgenic mice impairs survival of newborn neurons derived from adult hippocampal neurogenesis. J Neurosci 27:6771–6780PubMedCrossRefGoogle Scholar
  52. 52.
    Vivar C, Potter MC, Choi J, Lee JY, Stringer TP, Callaway EM, Gage FH, Suh H, Van PH (2012) Monosynaptic inputs to new neurons in the dentate gyrus. Nat Commun 3:1107PubMedCrossRefGoogle Scholar
  53. 53.
    Wang X, Lambert NA (2003) Membrane properties of identified lateral and medial perforant pathway projection neurons. Neuroscience 117:485–492PubMedCrossRefGoogle Scholar
  54. 54.
    Wesson DW, Levy E, Nixon RA, Wilson DA (2010) Olfactory dysfunction correlates with amyloid-beta burden in an Alzheimer's disease mouse model. J Neurosci 30:505–514PubMedCentralPubMedCrossRefGoogle Scholar
  55. 55.
    White JA, Alonso A, Kay AR (1993) A heart-like Na+ current in the medial entorhinal cortex. Neuron 11:1037–1047PubMedCrossRefGoogle Scholar
  56. 56.
    Wilson RS, Arnold SE, Schneider JA, Tang Y, Bennett DA (2007) The relationship between cerebral Alzheimer's disease pathology and odour identification in old age. J Neurol Neurosurg Psychiatry 78:30–35PubMedCentralPubMedCrossRefGoogle Scholar
  57. 57.
    Witter MP, Moser EI (2006) Spatial representation and the architecture of the entorhinal cortex. Trends Neurosci 29:671–678PubMedCrossRefGoogle Scholar
  58. 58.
    Wu W, Small SA (2006) Imaging the earliest stages of Alzheimer's disease. Curr Alzheimer Res 3:529–539PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2013

Authors and Affiliations

  1. 1.Institut de Pharmacologie Moléculaire et Cellulaire (IPMC), Centre National de la Recherche Scientifique (CNRS)Université de Nice Sophia AntipolisValbonneFrance
  2. 2.Department of Drug Science, Lab of Cellular & Molecular NeuroscienceUniversity of TurinTurinItaly

Personalised recommendations