title: Synapto-protective drugs evaluation in reconstructed neuronal network.
abstract: Chronic neurodegenerative syndromes such as Alzheimer's and Parkinson's diseases, or acute syndromes such as ischemic stroke or traumatic brain injuries are characterized by early synaptic collapse which precedes axonal and neuronal cell body degeneration and promotes early cognitive impairment in patients. Until now, neuroprotective strategies have failed to impede the progression of neurodegenerative syndromes. Drugs preventing the loss of cell body do not prevent the cognitive decline, probably because they lack synapto-protective effects. The absence of physiologically realistic neuronal network models which can be easily handled has hindered the development of synapto-protective drugs suitable for therapies. Here we describe a new microfluidic platform which makes it possible to study the consequences of axonal trauma of reconstructed oriented mouse neuronal networks. Each neuronal population and sub-compartment can be chemically addressed individually. The somatic, mid axon, presynaptic and postsynaptic effects of local pathological stresses or putative protective molecules can thus be evaluated with the help of this versatile "brain on chip" platform. We show that presynaptic loss is the earliest event observed following axotomy of cortical fibers, before any sign of axonal fragmentation or post-synaptic spine alteration. This platform can be used to screen and evaluate the synapto-protective potential of several drugs. For instance, NAD⁺ and the Rho-kinase inhibitor Y27632 can efficiently prevent synaptic disconnection, whereas the broad-spectrum caspase inhibitor zVAD-fmk and the stilbenoid resveratrol do not prevent presynaptic degeneration. Hence, this platform is a promising tool for fundamental research in the field of developmental and neurodegenerative neurosciences, and also offers the opportunity to set up pharmacological screening of axon-protective and synapto-protective drugs.
authors: Neurobiologie des Processus Adaptatifs, CNRS, UMR7102, Paris, France ; Université Pierre et Marie Curie, Paris, France.
authors: Bérangère
authors: B
authors: Deleglise
authors: Benjamin
authors: B
authors: Lassus
authors: Vaneyssa
authors: V
authors: Soubeyre
authors: Aurélie
authors: A
authors: Alleaume-Butaux
authors: Johannes J
authors: JJ
authors: Hjorth
authors: Maéva
authors: M
authors: Vignes
authors: Benoit
authors: B
authors: Schneider
authors: Bernard
authors: B
authors: Brugg
authors: Jean-Louis
authors: JL
authors: Viovy
authors: Jean-Michel
authors: JM
authors: Peyrin
mesh_terms: D000577:Amides / Q000494:pharmacology*; D000590:Amino Acid Chloromethyl Ketones / Q000494:pharmacology; D000818:Animals; D001369:Axons / Q000187:drug effects / Q000502:physiology / Q000648:ultrastructure; D003712:Dendrites / Q000187:drug effects / Q000502:physiology / Q000648:ultrastructure; D004622:Embryo, Mammalian; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D051379:Mice; D044085:Microfluidics / Q000295:instrumentation / Q000379:methods*; D008856:Microscopy, Fluorescence; D008959:Models, Neurological; D009243:NAD / Q000494:pharmacology*; D009415:Nerve Net / Q000187:drug effects* / Q000502:physiology; D019636:Neurodegenerative Diseases / Q000473:pathology / Q000517:prevention & control; D061251:Primary Cell Culture; D011725:Pyridines / Q000494:pharmacology*; D000077185:Resveratrol; D013267:Stilbenes / Q000494:pharmacology; D013569:Synapses / Q000187:drug effects* / Q000502:physiology / Q000648:ultrastructure
chemical_list: D000577:Amides; D000590:Amino Acid Chloromethyl Ketones; D004791:Enzyme Inhibitors; D011725:Pyridines; D013267:Stilbenes; C096713:benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone; D009243:NAD; C108830:Y 27632; D000077185:Resveratrol
references: Neuron. 2010 Apr 15;66(1):57-68
references: 20399729
references: Acta Neuropathol. 2009 Jul;118(1):5-36
references: 19381658
references: Mech Dev. 1998 Aug;76(1-2):79-90
references: 9867352
references: Cell Tissue Res. 2004 Oct;318(1):121-34
references: 15338272
references: Brain. 2006 Jun;129(Pt 6):1546-56
references: 16738060
references: Nature. 2009 Apr 23;458(7241):1056-60
references: 19262508
references: Neurotox Res. 2011 Jan;19(1):149-61
references: 20162389
references: J Neurosci Methods. 2011 Feb 15;195(2):185-93
references: 21167201
references: Neuroscientist. 2007 Oct;13(5):454-69
references: 17901255
references: Nature. 1997 Oct 30;389(6654):990-4
references: 9353125
references: Neuron. 2011 May 26;70(4):758-72
references: 21609830
references: Cell. 2010 May 28;141(5):859-71
references: 20510932
references: Neuron. 2013 Jan 23;77(2):219-34
references: 23352159
references: Yale J Biol Med. 2012 Dec;85(4):501-21
references: 23239951
references: Neuroscience. 2008 May 15;153(3):645-53
references: 18407419
references: Biochem Biophys Res Commun. 2007 Aug 3;359(3):665-71
references: 17560549
references: Adv Exp Med Biol. 2012;970:573-601
references: 22351073
references: Brain Pathol. 2008 Oct;18(4):484-96
references: 18371174
references: Neuron. 2012 Mar 22;73(6):1204-15
references: 22445347
references: J Neurosci. 2000 Feb 15;20(4):1333-41
references: 10662823
references: Nature. 2010 Mar 25;464(7288):529-35
references: 20336135
references: Neuron. 2009 Apr 16;62(1):42-52
references: 19376066
references: J Anat. 2003 Sep;203(3):265-76
references: 14529044
references: J Neurosci. 1993 Oct;13(10):4354-60
references: 8410191
references: Adv Exp Med Biol. 2012;970:553-72
references: 22351072
references: Neuron. 2006 Jun 15;50(6):819-21
references: 16772165
references: PLoS Genet. 2012;8(8):e1002936
references: 22952455
references: Acta Neuropathol. 2006 Oct;112(4):389-404
references: 16906426
references: Cell Death Differ. 2003 Feb;10(2):260-1
references: 12700655
references: Science. 2004 Aug 13;305(5686):1010-3
references: 15310905
references: J Neurosci. 2009 Jan 21;29(3):653-68
references: 19158292
references: Trends Neurosci. 2012 Dec;35(12):752-61
references: 23031246
references: Nat Methods. 2005 Aug;2(8):599-605
references: 16094385
references: Science. 2002 May 3;296(5569):868-71
references: 11988563
references: Nature. 2000 Oct 12;407(6805):802-9
references: 11048732
references: Proc Natl Acad Sci U S A. 2007 Apr 24;104(17):7217-22
references: 17438283
references: Nature. 2001 Mar 8;410(6825):227-30
references: 11242085
references: PLoS One. 2012;7(10):e47552
references: 23115653
references: Adv Exp Med Biol. 2012;970:493-516
references: 22351070
references: J Neurosci. 2012 Jan 4;32(1):68-84
references: 22219271
references: J Physiol. 2001 Aug 1;534(Pt 3):627-39
references: 11483696
references: Acta Neuropathol. 2009 Jul;118(1):167-79
references: 19390859
references: Brain. 2003 Mar;126(Pt 3):515-30
references: 12566274
references: Neuroscientist. 2010 Feb;16(1):19-27
references: 19359668
references: Lab Chip. 2011 Nov 7;11(21):3663-73
references: 21922081