Skip to main content
Top
Published in: Brain Structure and Function 3/2015

01-05-2015 | Original Article

Implications of p75NTR for dentate gyrus morphology and hippocampus-related behavior revisited

Authors: M. Dokter, R. Busch, R. Poser, M. A. Vogt, V. von Bohlen und Halbach, P. Gass, K. Unsicker, O. von Bohlen und Halbach

Published in: Brain Structure and Function | Issue 3/2015

Login to get access

Abstract

The pan-neurotrophin receptor p75NTR is expressed in the adult brain in a discrete pattern. Although numerous studies have addressed its implications for hippocampal functions, the generated sets of data are surprisingly conflicting. We have therefore set out to re-investigate the impact of a deletion of the full-length p75NTR receptor on several parameters of the dentate gyrus (DG), including neurogenesis and hippocampus-related behavior by using p75NTRExIII knockout mice. Moreover, we investigated further parameters of the DG (cholinergic innervation, dendritic spines). In addition, we analyzed on the morphological level the impact of aging by comparing adult and aged p75NTRExIII mice and their age-matched littermates. Adult (4–6 months old), but not aged (20 months old), p75NTRExIII knockout mice display an enhanced volume of the DG. However, adult neurogenesis within the adult DG was unaffected in both adult and aged p75NTRExIII knockout mice. We could further demonstrate that the change in the volume of the DG was accompanied by an increased cholinergic innervation and increased spine densities of granule cells in adult, but not aged p75NTR deficient mice. These morphological changes in the adult p75NTR deficient mice were accompanied by specific alterations in their behavior, including altered behavior in the Morris water maze test, indicating impairments in spatial memory retention.
Literature
go back to reference Barrett GL, Reid CA, Tsafoulis C, Zhu W, Williams DA, Paolini AG, Trieu J, Murphy M (2010) Enhanced spatial memory and hippocampal long-term potentiation in p75 neurotrophin receptor knockout mice. Hippocampus 20(1):145–152. doi:10.1002/hipo.20598 PubMed Barrett GL, Reid CA, Tsafoulis C, Zhu W, Williams DA, Paolini AG, Trieu J, Murphy M (2010) Enhanced spatial memory and hippocampal long-term potentiation in p75 neurotrophin receptor knockout mice. Hippocampus 20(1):145–152. doi:10.​1002/​hipo.​20598 PubMed
go back to reference Baryshnikova LM, von Bohlen und Halbach O, Kaplan S, von Bartheld CS (2006) Two distinct events, section compression and loss of particles (“lost caps”), contribute to z-axis distortion and bias in optical disector counting. Microsc Res Tech 69(9):738–756. doi:10.1002/jemt.20345 CrossRefPubMed Baryshnikova LM, von Bohlen und Halbach O, Kaplan S, von Bartheld CS (2006) Two distinct events, section compression and loss of particles (“lost caps”), contribute to z-axis distortion and bias in optical disector counting. Microsc Res Tech 69(9):738–756. doi:10.​1002/​jemt.​20345 CrossRefPubMed
go back to reference Chourbaji S, Hellweg R, Brandis D, Zorner B, Zacher C, Lang UE, Henn FA, Hortnagl H, Gass P (2004) Mice with reduced brain-derived neurotrophic factor expression show decreased choline acetyltransferase activity, but regular brain monoamine levels and unaltered emotional behavior. Brain Res Mol Brain Res 121(1–2):28–36. doi:10.1016/j.molbrainres.2003.11.002 CrossRefPubMed Chourbaji S, Hellweg R, Brandis D, Zorner B, Zacher C, Lang UE, Henn FA, Hortnagl H, Gass P (2004) Mice with reduced brain-derived neurotrophic factor expression show decreased choline acetyltransferase activity, but regular brain monoamine levels and unaltered emotional behavior. Brain Res Mol Brain Res 121(1–2):28–36. doi:10.​1016/​j.​molbrainres.​2003.​11.​002 CrossRefPubMed
go back to reference Dokter M, von Bohlen und Halbach O (2012) Neurogenesis within the adult hippocampus under physiological conditions and in depression. Neural Regen Res 7(7):8. doi:10.3969/j Dokter M, von Bohlen und Halbach O (2012) Neurogenesis within the adult hippocampus under physiological conditions and in depression. Neural Regen Res 7(7):8. doi:10.​3969/​j
go back to reference Freund M, Walther T, von Bohlen Und Halbach O (2013) Effects of the angiotensin-(1-7) receptor Mas on cell proliferation and on the population of doublecortin positive cells within the dentate gyrus and the piriform cortex. Eur Neuropsychopharmacol. doi:10.1016/j.euroneuro.2013.06.004 PubMed Freund M, Walther T, von Bohlen Und Halbach O (2013) Effects of the angiotensin-(1-7) receptor Mas on cell proliferation and on the population of doublecortin positive cells within the dentate gyrus and the piriform cortex. Eur Neuropsychopharmacol. doi:10.​1016/​j.​euroneuro.​2013.​06.​004 PubMed
go back to reference Friedman WJ (2000) Neurotrophins induce death of hippocampal neurons via the p75 receptor. J Neurosci 20(17):6340–6346PubMed Friedman WJ (2000) Neurotrophins induce death of hippocampal neurons via the p75 receptor. J Neurosci 20(17):6340–6346PubMed
go back to reference Fujii T, Kunugi H (2009) p75NTR as a therapeutic target for neuropsychiatric diseases. Curr Mol Pharmacol 2:70–76CrossRefPubMed Fujii T, Kunugi H (2009) p75NTR as a therapeutic target for neuropsychiatric diseases. Curr Mol Pharmacol 2:70–76CrossRefPubMed
go back to reference Gascon E, Vutskits L, Jenny B, Durbec P, Kiss JZ (2007) PSA-NCAM in postnatally generated immature neurons of the olfactory bulb: a crucial role in regulating p75 expression and cell survival. Development 134(6):1181–1190. doi:10.1242/dev.02808 CrossRefPubMed Gascon E, Vutskits L, Jenny B, Durbec P, Kiss JZ (2007) PSA-NCAM in postnatally generated immature neurons of the olfactory bulb: a crucial role in regulating p75 expression and cell survival. Development 134(6):1181–1190. doi:10.​1242/​dev.​02808 CrossRefPubMed
go back to reference Greferath U, Bennie A, Kourakis A, Bartlett PF, Murphy M, Barrett GL (2000) Enlarged cholinergic forebrain neurons and improved spatial learning in p75 knockout mice. Eur J Neurosci 12(3):885–893CrossRefPubMed Greferath U, Bennie A, Kourakis A, Bartlett PF, Murphy M, Barrett GL (2000) Enlarged cholinergic forebrain neurons and improved spatial learning in p75 knockout mice. Eur J Neurosci 12(3):885–893CrossRefPubMed
go back to reference Hefti F, Will B (1987) Nerve growth factor is a neurotrophic factor for forebrain cholinergic neurons; implications for Alzheimer’s disease. J Neural Transm Suppl 24:309–315PubMed Hefti F, Will B (1987) Nerve growth factor is a neurotrophic factor for forebrain cholinergic neurons; implications for Alzheimer’s disease. J Neural Transm Suppl 24:309–315PubMed
go back to reference Karl T, Pabst R, von Horsten S (2003) Behavioral phenotyping of mice in pharmacological and toxicological research. Exp Toxicol Pathol 55(1):69–83CrossRefPubMed Karl T, Pabst R, von Horsten S (2003) Behavioral phenotyping of mice in pharmacological and toxicological research. Exp Toxicol Pathol 55(1):69–83CrossRefPubMed
go back to reference Lee KF, Li E, Huber LJ, Landis SC, Sharpe AH, Chao MV, Jaenisch R (1992) Targeted mutation of the gene encoding the low affinity NGF receptor p75 leads to deficits in the peripheral sensory nervous system. Cell 69(5):737–749CrossRefPubMed Lee KF, Li E, Huber LJ, Landis SC, Sharpe AH, Chao MV, Jaenisch R (1992) Targeted mutation of the gene encoding the low affinity NGF receptor p75 leads to deficits in the peripheral sensory nervous system. Cell 69(5):737–749CrossRefPubMed
go back to reference Mufson EJ, Ginsberg SD, Ikonomovic MD, DeKosky ST (2003) Human cholinergic basal forebrain: chemoanatomy and neurologic dysfunction. J Chem Neuroanat 26(4):233–242CrossRefPubMed Mufson EJ, Ginsberg SD, Ikonomovic MD, DeKosky ST (2003) Human cholinergic basal forebrain: chemoanatomy and neurologic dysfunction. J Chem Neuroanat 26(4):233–242CrossRefPubMed
go back to reference Naumann T, Casademunt E, Hollerbach E, Hofmann J, Dechant G, Frotscher M, Barde YA (2002) Complete deletion of the neurotrophin receptor p75NTR leads to long-lasting increases in the number of basal forebrain cholinergic neurons. J Neurosci 22(7):2409–2418PubMed Naumann T, Casademunt E, Hollerbach E, Hofmann J, Dechant G, Frotscher M, Barde YA (2002) Complete deletion of the neurotrophin receptor p75NTR leads to long-lasting increases in the number of basal forebrain cholinergic neurons. J Neurosci 22(7):2409–2418PubMed
go back to reference Peterson DA, Dickinson-Anson HA, Leppert JT, Lee KF, Gage FH (1999) Central neuronal loss and behavioral impairment in mice lacking neurotrophin receptor p75. J Comp Neurol 404(1):1–20CrossRefPubMed Peterson DA, Dickinson-Anson HA, Leppert JT, Lee KF, Gage FH (1999) Central neuronal loss and behavioral impairment in mice lacking neurotrophin receptor p75. J Comp Neurol 404(1):1–20CrossRefPubMed
go back to reference Rogers DC, Jones DN, Nelson PR, Jones CM, Quilter CA, Robinson TL, Hagan JJ (1999) Use of SHIRPA and discriminant analysis to characterise marked differences in the behavioural phenotype of six inbred mouse strains. Behav Brain Res 105(2):207–217CrossRefPubMed Rogers DC, Jones DN, Nelson PR, Jones CM, Quilter CA, Robinson TL, Hagan JJ (1999) Use of SHIRPA and discriminant analysis to characterise marked differences in the behavioural phenotype of six inbred mouse strains. Behav Brain Res 105(2):207–217CrossRefPubMed
go back to reference Teng HK, Teng KK, Lee R, Wright S, Tevar S, Almeida RD, Kermani P, Torkin R, Chen ZY, Lee FS, Kraemer RT, Nykjaer A, Hempstead BL (2005) ProBDNF induces neuronal apoptosis via activation of a receptor complex of p75NTR and sortilin. J Neurosci 25(22):5455–5463. doi:10.1523/jneurosci.5123-04.2005 CrossRefPubMed Teng HK, Teng KK, Lee R, Wright S, Tevar S, Almeida RD, Kermani P, Torkin R, Chen ZY, Lee FS, Kraemer RT, Nykjaer A, Hempstead BL (2005) ProBDNF induces neuronal apoptosis via activation of a receptor complex of p75NTR and sortilin. J Neurosci 25(22):5455–5463. doi:10.​1523/​jneurosci.​5123-04.​2005 CrossRefPubMed
go back to reference Van der Zee CE, Ross GM, Riopelle RJ, Hagg T (1996) Survival of cholinergic forebrain neurons in developing p75NGFR-deficient mice. Science 274(5293):1729–1732CrossRefPubMed Van der Zee CE, Ross GM, Riopelle RJ, Hagg T (1996) Survival of cholinergic forebrain neurons in developing p75NGFR-deficient mice. Science 274(5293):1729–1732CrossRefPubMed
go back to reference von Bartheld C (2002) Counting particles in tissue sections: choices of methods and importance of calibration to minimize biases. Histol Histopathol 17(2):639–648 von Bartheld C (2002) Counting particles in tissue sections: choices of methods and importance of calibration to minimize biases. Histol Histopathol 17(2):639–648
go back to reference von Bohlen und Halbach O, Unsicker K (2003) Age-related decline in the tyrosine hydroxylase-immunoreactive innervation of the amygdala and dentate gyrus in mice. Cell Tissue Res 311(2):139–143. doi:10.1007/s00441-002-0662-4 von Bohlen und Halbach O, Unsicker K (2003) Age-related decline in the tyrosine hydroxylase-immunoreactive innervation of the amygdala and dentate gyrus in mice. Cell Tissue Res 311(2):139–143. doi:10.​1007/​s00441-002-0662-4
go back to reference von Bohlen und Halbach O, Minichiello L, Unsicker K (2005) Haploinsufficiency for trkB and trkC receptors induces cell loss and accumulation of alpha-synuclein in the substantia nigra. FASEB J 19(12):1740–1742. doi:10.1096/fj.05-3845fje von Bohlen und Halbach O, Minichiello L, Unsicker K (2005) Haploinsufficiency for trkB and trkC receptors induces cell loss and accumulation of alpha-synuclein in the substantia nigra. FASEB J 19(12):1740–1742. doi:10.​1096/​fj.​05-3845fje
go back to reference von Bohlen und Halbach O, Krause S, Medina D, Sciarretta C, Minichiello L, Unsicker K (2006a) Regional- and age-dependent reduction in trkB receptor expression in the hippocampus is associated with altered spine morphologies. Biol Psychiatry 59(9):793–800. doi:10.1016/j.biopsych.2005.08.025 von Bohlen und Halbach O, Krause S, Medina D, Sciarretta C, Minichiello L, Unsicker K (2006a) Regional- and age-dependent reduction in trkB receptor expression in the hippocampus is associated with altered spine morphologies. Biol Psychiatry 59(9):793–800. doi:10.​1016/​j.​biopsych.​2005.​08.​025
go back to reference von Bohlen und Halbach O, Zacher C, Gass P, Unsicker K (2006b) Age-related alterations in hippocampal spines and deficiencies in spatial memory in mice. J Neurosci Res 83(4):525–531. doi:10.1002/jnr.20759 CrossRef von Bohlen und Halbach O, Zacher C, Gass P, Unsicker K (2006b) Age-related alterations in hippocampal spines and deficiencies in spatial memory in mice. J Neurosci Res 83(4):525–531. doi:10.​1002/​jnr.​20759 CrossRef
go back to reference von Schack D, Casademunt E, Schweigreiter R, Meyer M, Bibel M, Dechant G (2001) Complete ablation of the neurotrophin receptor p75NTR causes defects both in the nervous and the vascular system. Nat Neurosci 4(10):977–978. doi:10.1038/nn730 CrossRef von Schack D, Casademunt E, Schweigreiter R, Meyer M, Bibel M, Dechant G (2001) Complete ablation of the neurotrophin receptor p75NTR causes defects both in the nervous and the vascular system. Nat Neurosci 4(10):977–978. doi:10.​1038/​nn730 CrossRef
go back to reference Waltereit R, Leimer U, von Bohlen und Halbach O, Panke J, Holter SM, Garrett L, Wittig K, Schneider M, Schmitt C, Calzada-Wack J, Neff F, Becker L, Prehn C, Kutscherjawy S, Endris V, Bacon C, Fuchs H, Gailus-Durner V, Berger S, Schonig K, Adamski J, Klopstock T, Esposito I, Wurst W, de Angelis MH, Rappold G, Wieland T, Bartsch D (2012) Srgap3−/− mice present a neurodevelopmental disorder with schizophrenia-related intermediate phenotypes. FASEB J 26(11):4418–4428. doi:10.1096/fj.11-202317 Waltereit R, Leimer U, von Bohlen und Halbach O, Panke J, Holter SM, Garrett L, Wittig K, Schneider M, Schmitt C, Calzada-Wack J, Neff F, Becker L, Prehn C, Kutscherjawy S, Endris V, Bacon C, Fuchs H, Gailus-Durner V, Berger S, Schonig K, Adamski J, Klopstock T, Esposito I, Wurst W, de Angelis MH, Rappold G, Wieland T, Bartsch D (2012) Srgap3−/− mice present a neurodevelopmental disorder with schizophrenia-related intermediate phenotypes. FASEB J 26(11):4418–4428. doi:10.​1096/​fj.​11-202317
go back to reference Ward NL, Stanford LE, Brown RE, Hagg T (2000) Cholinergic medial septum neurons do not degenerate in aged 129/Sv control or p75(NGFR)−/−mice. Neurobiol Aging 21(1):125–134CrossRefPubMed Ward NL, Stanford LE, Brown RE, Hagg T (2000) Cholinergic medial septum neurons do not degenerate in aged 129/Sv control or p75(NGFR)−/−mice. Neurobiol Aging 21(1):125–134CrossRefPubMed
go back to reference Yeo TT, Chua-Couzens J, Butcher LL, Bredesen DE, Cooper JD, Valletta JS, Mobley WC, Longo FM (1997) Absence of p75NTR causes increased basal forebrain cholinergic neuron size, choline acetyltransferase activity, and target innervation. J Neurosci 17(20):7594–7605PubMed Yeo TT, Chua-Couzens J, Butcher LL, Bredesen DE, Cooper JD, Valletta JS, Mobley WC, Longo FM (1997) Absence of p75NTR causes increased basal forebrain cholinergic neuron size, choline acetyltransferase activity, and target innervation. J Neurosci 17(20):7594–7605PubMed
Metadata
Title
Implications of p75NTR for dentate gyrus morphology and hippocampus-related behavior revisited
Authors
M. Dokter
R. Busch
R. Poser
M. A. Vogt
V. von Bohlen und Halbach
P. Gass
K. Unsicker
O. von Bohlen und Halbach
Publication date
01-05-2015
Publisher
Springer Berlin Heidelberg
Published in
Brain Structure and Function / Issue 3/2015
Print ISSN: 1863-2653
Electronic ISSN: 1863-2661
DOI
https://doi.org/10.1007/s00429-014-0737-5

Other articles of this Issue 3/2015

Brain Structure and Function 3/2015 Go to the issue