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Molecular Neurodegeneration
Published in: Molecular Neurodegeneration 1/2013

Open Access 01-12-2013 | Research article

Aβ impairs nicotinic regulation of inhibitory synaptic transmission and interneuron excitability in prefrontal cortex

Authors: Guo-Jun Chen, Zhe Xiong, Zhen Yan

Published in: Molecular Neurodegeneration | Issue 1/2013

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Abstract

Background

Accumulation of β-amyloid (Aβ) and cholinergic deficiency are two prominent features of Alzheimer’s disease (AD). To understand how Aβ-induced dysfunction of the nicotinic system may contribute to cognitive impairment in AD, we examined the effect of Aβ on nicotinic regulation of synaptic transmission and neuronal excitability in prefrontal cortex (PFC), a brain region critical for cognitive processes.

Results

We found that activation of nicotinic acetylcholine receptors (nAChRs) with nicotine increased the inhibitory postsynaptic currents recorded in PFC pyramidal neurons, which was associated with the nicotine-induced increase in the excitability of PFC layer I GABAergic interneurons. Both effects of nicotine were disrupted by Aβ. However, Aβ did not impair nicotinic regulation of excitatory neurotransmission in PFC interneurons. The nicotinic effect on synaptic inhibition was also lost in transgenic mice with five familial Alzheimer’s disease mutations. Inhibiting PKC attenuated nicotinic regulation of inhibitory, but not excitatory, neurotransmission.

Conclusions

Our study suggests that Aβ selectively impairs nicotinic regulation of inhibitory inputs to PFC pyramidal neurons, which might be due to its interference with PKC activation. Thus, in the PFC circuits of AD, the balance between inhibition and excitation under the control of nAChRs may be disturbed by Aβ.
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Literature
1.
Esteban JA: Living with the enemy: a physiological role for the beta-amyloid peptide. Trends Neurosci. 2004, 27: 1-3. 10.1016/j.tins.2003.10.008.CrossRefPubMed
2.
Price DL, Sisodia SS: Mutant genes in familial alzheimer’s disease and transgenic models. Annu Rev Neurosci. 1998, 21: 479-505. 10.1146/annurev.neuro.21.1.479.CrossRefPubMed
3.
Selkoe DJ: Alzheimer’s disease: genes, proteins, and therapy. Physiol Rev. 2001, 81: 741-766.PubMed
4.
Tanzi RE, Bertram L: Twenty years of the alzheimer’s disease amyloid hypothesis: a genetic perspective. Cell. 2005, 120: 545-555. 10.1016/j.cell.2005.02.008.CrossRefPubMed
5.
Yankner BA, Duffy LK, Kirschner DA: Neurotrophic and neurotoxic effects of amyloid beta protein: reversal by tachykinin neuropeptides. Science. 1990, 250: 279-282. 10.1126/science.2218531.CrossRefPubMed
6.
Mattson MP: Cellular actions of beta-amyloid precursor protein and its soluble and fibrillogenic derivatives. Physiol Rev. 1997, 77: 1081-1132.PubMed
7.
Selkoe DJ: Alzheimer’s disease is a synaptic failure. Science. 2002, 298: 789-791. 10.1126/science.1074069.CrossRefPubMed
8.
Palop JJ, Chin J, Mucke L: A network dysfunction perspective on neurodegenerative diseases. Nature. 2006, 443: 768-773. 10.1038/nature05289.CrossRefPubMed
9.
Bartus RT, Dean RL, Beer B, Lippa AS: The cholinergic hypothesis of geriatric memory dysfunction. Science. 1982, 217: 408-414. 10.1126/science.7046051.CrossRefPubMed
10.
Paterson D, Nordberg A: Neuronal nicotinic receptors in the human brain. Prog Neurobiol. 2000, 61: 75-111. 10.1016/S0301-0082(99)00045-3.CrossRefPubMed
11.
Perry E, Martin-Ruiz C, Lee M, Griffiths M, Johnson M, Piggott M, Haroutunian V, Buxbaum JD, Nasland J, Davis K, Gotti C, Clementi F, Tzartos S, Cohen O, Soreq H, Jaros E, Perry R, Ballard C, McKeith I, Court J: Nicotinic receptor subtypes in human brain ageing, Alzheimer and lewy body diseases. Eur J Pharmacol. 2000, 393: 215-222. 10.1016/S0014-2999(00)00064-9.CrossRefPubMed
12.
Lena C, Changeux JP, Mulle C: Evidence for “preterminal” nicotinic receptors on GABAergic axons in the rat interpeduncular nucleus. J Neurosci. 1993, 13: 2680-2688.PubMed
13.
Zarei MM, Radcliffe KA, Chen D, Patrick JW, Dani JA: Distributions of nicotinic acetylcholine receptor alpha7 and beta2 subunits on cultured hippocampal neurons. Neuroscience. 1999, 88: 755-764. 10.1016/S0306-4522(98)00246-2.CrossRefPubMed
14.
Dani JA, Bertrand D: Nicotinic acetylcholine receptors and nicotinic cholinergic mechanisms of the central nervous system. Annu Rev Pharmacol Toxicol. 2007, 47: 699-729. 10.1146/annurev.pharmtox.47.120505.105214.CrossRefPubMed
15.
Levin ED, McClernon FJ, Rezvani AH: Nicotinic effects on cognitive function: behavioral characterization, pharmacological specification, and anatomic localization. Psychopharmacology (Berl). 2006, 184: 523-539. 10.1007/s00213-005-0164-7.CrossRef
16.
Nott A, Levin ED: Dorsal hippocampal alpha7 and alpha4beta2 nicotinic receptors and memory. Brain Res. 2006, 1081: 72-78. 10.1016/j.brainres.2006.01.052.CrossRefPubMed
17.
Grottick AJ, Higgins GA: Effect of subtype selective nicotinic compounds on attention as assessed by the five-choice serial reaction time task. Behav Brain Res. 2000, 117: 197-208. 10.1016/S0166-4328(00)00305-3.CrossRefPubMed
18.
Mirza NR, Stolerman IP: Nicotine enhances sustained attention in the rat under specific task conditions. Psychopharmacology (Berl). 1998, 138: 266-274. 10.1007/s002130050671.CrossRef
19.
Wilkinson DG, Francis PT, Schwam E, Payne-Parrish J: Cholinesterase inhibitors used in the treatment of Alzheimer’s disease: the relationship between pharmacological effects and clinical efficacy. Drugs Aging. 2004, 21: 453-478. 10.2165/00002512-200421070-00004.CrossRefPubMed
20.
Alkondon M, Pereira EF, Eisenberg HM, Albuquerque EX: Nicotinic receptor activation in human cerebral cortical interneurons: a mechanism for inhibition and disinhibition of neuronal networks. J Neurosci. 2000, 20: 66-75.PubMed
21.
Mansvelder HD, Keath JR, McGehee DS: Synaptic mechanisms underlie nicotine-induced excitability of brain reward areas. Neuron. 2002, 33: 905-919. 10.1016/S0896-6273(02)00625-6.CrossRefPubMed
22.
Lambe EK, Picciotto MR, Aghajanian GK: Nicotine induces glutamate release from thalamocortical terminals in prefrontal cortex. Neuropsychopharmacology. 2003, 28: 216-225. 10.1038/sj.npp.1300032.CrossRefPubMed
23.
Ohnishi M, Katsuki H, Takagi M, Kume T, Akaike A: Long-term treatment with nicotine suppresses neurotoxicity of, and microglial activation by, thrombin in cortico-striatal slice cultures. Eur J Pharmacol. 2009, 602: 288-293. 10.1016/j.ejphar.2008.11.041.CrossRefPubMed
24.
Chu Z, Galarreta M, Hestrin S: Synaptic interactions of late-spiking neocortical neurons in layer 1. J Neurosci. 2003, 23: 96-102.PubMed
25.
Zhu Y, Zhu JJ: Rapid arrival and integration of ascending sensory information in layer 1 nonpyramidal neurons and tuft dendrites of layer 5 pyramidal neurons of the neocortex. J Neurosci. 2004, 24: 1272-1279. 10.1523/JNEUROSCI.4805-03.2004.CrossRefPubMed
26.
Zhou FM, Hablitz JJ: Layer I neurons of rat neocortex. I. Action potential and repetitive firing properties. J Neurophysiol. 1996, 76: 651-667.PubMed
27.
Tu B, Gu Z, Shen JX, Lamb PW, Yakel JL: Characterization of a nicotine-sensitive neuronal population in rat entorhinal cortex. J Neurosci. 2009, 29: 10436-10448. 10.1523/JNEUROSCI.2580-09.2009.PubMedCentralCrossRefPubMed
28.
Gu Z, Liu W, Yan Z: β-amyloid impairs AMPA receptor trafficking and function by reducing CaMKII synaptic distribution. J Biol Chem. 2009, 284: 10639-10649. 10.1074/jbc.M806508200.PubMedCentralCrossRefPubMed
29.
Gu Z, Yakel JL: Timing-dependent septal cholinergic induction of dynamic hippocampal synaptic plasticity. Neuron. 2011, 71: 155-165. 10.1016/j.neuron.2011.04.026.PubMedCentralCrossRefPubMed
30.
Liu W, Dou F, Feng J, Yan Z: RACK1 is involved in β-amyloid impairment of muscarinic regulation of GABAergic transmission. Neurobiol Aging. 2011, 32: 1818-1826. 10.1016/j.neurobiolaging.2009.10.017.PubMedCentralCrossRefPubMed
31.
Oakley H, Cole SL, Logan S, Maus E, Shao P, Craft J, Guillozet-Bongaarts A, Ohno M, Disterhoft J, Van Eldik L, Berry R, Vassar R: Intraneuronal beta-amyloid aggregates, neurodegeneration, and neuron loss in transgenic mice with five familial Alzheimer’s disease mutations: potential factors in amyloid plaque formation. J Neurosci. 2006, 26: 10129-10140. 10.1523/JNEUROSCI.1202-06.2006.CrossRefPubMed
32.
Tyszkiewicz JP, Yan Z: β-amyloid peptides impair PKC-dependent functions of metabotropic glutamate receptors in prefrontal cortical neurons. J Neurophysiology. 2005, 93: 3102-3111. 10.1152/jn.00939.2004.CrossRefPubMed
33.
Zhong P, Gu Z, Wang X, Jiang H, Feng J, Yan Z: Impaired modulation of GABAergic transmission by muscarinic receptors in a mouse transgenic model of Alzheimer’s disease. J Biol Chem. 2003, 278: 26888-26896. 10.1074/jbc.M302789200.CrossRefPubMed
34.
Frazier CJ, Rollins YD, Breese CR, Leonard S, Freedman R, Dunwiddie TV: Acetylcholine activates an alpha-bungarotoxin-sensitive nicotinic current in rat hippocampal interneurons, but not pyramidal cells. J Neurosci. 1998, 18: 1187-1195.PubMed
35.
Zhang H, Sulzer D: Frequency-dependent modulation of dopamine release by nicotine. Nat Neurosci. 2004, 7: 581-582. 10.1038/nn1243.CrossRefPubMed
36.
Couey JJ, Meredith RM, Spijker S, Poorthuis RB, Smit AB, Brussaard AB, Mansvelder HD: Distributed network actions by nicotine increase the threshold for spike-timing-dependent plasticity in prefrontal cortex. Neuron. 2007, 54: 73-87. 10.1016/j.neuron.2007.03.006.CrossRefPubMed
37.
Xu J, Zhu Y, Heinemann SF: Identification of sequence motifs that target neuronal nicotinic receptors to dendrites and axons. J Neurosci. 2006, 26: 9780-9793. 10.1523/JNEUROSCI.0840-06.2006.CrossRefPubMed
38.
Sher E, Chen Y, Sharples TJ, Broad LM, Benedetti G, Zwart R, McPhie GI, Pearson KH, Baldwinson T, De Filippi G: Physiological roles of neuronal nicotinic receptor subtypes: new insights on the nicotinic modulation of neurotransmitter release, synaptic transmission and plasticity. Curr Top Med Chem. 2004, 4: 283-297. 10.2174/1568026043451393.CrossRefPubMed
39.
Wonnacott S: Presynaptic nicotinic ACh receptors. Trends Neurosci. 1997, 20: 92-98. 10.1016/S0166-2236(96)10073-4.CrossRefPubMed
40.
Alkondon M, Pereira EF, Barbosa CT, Albuquerque EX: Neuronal nicotinic acetylcholine receptor activation modulates gamma-aminobutyric acid release from CA1 neurons of rat hippocampal slices. J Pharmacol Exp Ther. 1997, 283: 1396-1411.PubMed
41.
Mameli-Engvall M, Evrard A, Pons S, Maskos U, Svensson TH, Changeux JP, Faure P: Hierarchical control of dopamine neuron-firing patterns by nicotinic receptors. Neuron. 2006, 50: 911-921. 10.1016/j.neuron.2006.05.007.CrossRefPubMed
42.
Dineley KT: Beta-amyloid peptide–nicotinic acetylcholine receptor interaction: the two faces of health and disease. Front Biosci. 2007, 12: 5030-5038. 10.2741/2445.CrossRefPubMed
43.
Oddo S, LaFerla FM: The role of nicotinic acetylcholine receptors in Alzheimer’s disease. J Physiol Paris. 2006, 99: 172-179. 10.1016/j.jphysparis.2005.12.080.CrossRefPubMed
44.
Pettit DL, Shao Z, Yakel JL: Beta-Amyloid(1–42) peptide directly modulates nicotinic receptors in the rat hippocampal slice. J Neurosci. 2001, 21: RC120-PubMed
45.
Liu Q, Kawai H, Berg DK: Beta -amyloid peptide blocks the response of alpha 7-containing nicotinic receptors on hippocampal neurons. Proc Natl Acad Sci U S A. 2001, 98: 4734-4739. 10.1073/pnas.081553598.PubMedCentralCrossRefPubMed
46.
Spencer JP, Weil A, Hill K, Hussain I, Richardson JC, Cusdin FS, Chen YH, Randall AD: Transgenic mice over-expressing human beta-amyloid have functional nicotinic alpha 7 receptors. Neuroscience. 2006, 137: 795-805. 10.1016/j.neuroscience.2005.10.007.CrossRefPubMed
47.
Dougherty JJ, Wu J, Nichols RA: Beta-amyloid regulation of presynaptic nicotinic receptors in rat hippocampus and neocortex. J Neurosci. 2003, 23: 6740-6747.PubMed
48.
Klein RC, Yakel JL: Paired-pulse potentiation of alpha7-containing nAChRs in rat hippocampal CA1 stratum radiatum interneurones. J Physiol. 2005, 568: 881-889. 10.1113/jphysiol.2005.096081.PubMedCentralCrossRefPubMed
49.
Wanaverbecq N, Semyanov A, Pavlov I, Walker MC, Kullmann DM: Cholinergic axons modulate GABAergic signaling among hippocampal interneurons via postsynaptic alpha 7 nicotinic receptors. J Neurosci. 2007, 27: 5683-5693. 10.1523/JNEUROSCI.1732-07.2007.PubMedCentralCrossRefPubMed
50.
Alkon DL, Sun MK, Nelson TJ: PKC signaling deficits: a mechanistic hypothesis for the origins of Alzheimer’s disease. Trends Pharmacol Sci. 2007, 28: 51-60. 10.1016/j.tips.2006.12.002.CrossRefPubMed
51.
Sun MK, Alkon DL: Bryostatin-1: pharmacology and therapeutic potential as a CNS drug. CNS Drug Rev. 2006, 12: 1-8. 10.1111/j.1527-3458.2006.00001.x.CrossRefPubMed
52.
Youdim MB, Weinstock M: Molecular basis of neuroprotective activities of rasagiline and the anti-Alzheimer drug TV3326 [(N-propargyl-(3R)aminoindan-5-YL)-ethyl methyl carbamate]. Cell Mol Neurobiol. 2001, 21: 555-573. 10.1023/A:1015131516649.CrossRefPubMed
53.
Galarreta M, Hestrin S: Frequency-dependent synaptic depression and the balance of excitation and inhibition in the neocortex. Nat Neurosci. 1998, 1: 587-594. 10.1038/2882.CrossRefPubMed
54.
Galarreta M, Hestrin S: A network of fast-spiking cells in the neocortex connected by electrical synapses. Nature. 1999, 402: 72-75. 10.1038/47029.CrossRefPubMed
55.
Whittington MA, Traub RD: Interneuron diversity series: inhibitory interneurons and network oscillations in vitro. Trends Neurosci. 2003, 26: 676-682. 10.1016/j.tins.2003.09.016.CrossRefPubMed
56.
Howard MW, Rizzuto DS, Caplan JB, Madsen JR, Lisman J, Aschenbrenner-Scheibe R, Schulze-Bonhage A, Kahana MJ: Gamma oscillations correlate with working memory load in humans. Cereb Cortex. 2003, 13: 1369-1374. 10.1093/cercor/bhg084.CrossRefPubMed
57.
Dahlgren KN, Manelli AM, Stine WB, Baker LK, Krafft GA, LaDu MJ: Oligomeric and fibrillar species of amyloid-beta peptides differentially affect neuronal viability. J Biol Chem. 2002, 277: 32046-32053. 10.1074/jbc.M201750200.CrossRefPubMed
58.
Feng J, Cai X, Zhao J, Yan Z: Serotonin receptors modulate GABA(A) receptor channels through activation of anchored protein kinase C in prefrontal cortical neurons. J Neurosci. 2001, 21: 6502-6511.PubMed
59.
Chen G, Kittler JT, Moss SJ, Yan Z: Dopamine D3 receptors regulate GABAA receptor function through a phospho-dependent endocytosis mechanism in nucleus accumbens. J Neurosci. 2006, 26: 2513-2521. 10.1523/JNEUROSCI.4712-05.2006.CrossRefPubMed
Metadata
Title
Aβ impairs nicotinic regulation of inhibitory synaptic transmission and interneuron excitability in prefrontal cortex
Authors
Guo-Jun Chen
Zhe Xiong
Zhen Yan
Publication date
01-12-2013
Publisher
BioMed Central
Published in
Molecular Neurodegeneration / Issue 1/2013
Electronic ISSN: 1750-1326
DOI
https://doi.org/10.1186/1750-1326-8-3

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