Synapto-protective drugs evaluation in reconstructed neuronal network

PLoS One. 2013 Aug 16;8(8):e71103. doi: 10.1371/journal.pone.0071103. eCollection 2013.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amides / pharmacology*
  • Amino Acid Chloromethyl Ketones / pharmacology
  • Animals
  • Axons / drug effects
  • Axons / physiology
  • Axons / ultrastructure
  • Dendrites / drug effects
  • Dendrites / physiology
  • Dendrites / ultrastructure
  • Embryo, Mammalian
  • Enzyme Inhibitors / pharmacology*
  • Mice
  • Microfluidics / instrumentation
  • Microfluidics / methods*
  • Microscopy, Fluorescence
  • Models, Neurological
  • NAD / pharmacology*
  • Nerve Net / drug effects*
  • Nerve Net / physiology
  • Neurodegenerative Diseases / pathology
  • Neurodegenerative Diseases / prevention & control
  • Primary Cell Culture
  • Pyridines / pharmacology*
  • Resveratrol
  • Stilbenes / pharmacology
  • Synapses / drug effects*
  • Synapses / physiology
  • Synapses / ultrastructure


  • Amides
  • Amino Acid Chloromethyl Ketones
  • Enzyme Inhibitors
  • Pyridines
  • Stilbenes
  • benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone
  • NAD
  • Y 27632
  • Resveratrol

Grants and funding

This work was supported by the French Research National Agency “Agence Nationale de la Recherche,” ANR RPIB “Neuroscreen” and ANR “PrionsensiTNF.” BD was supported by a PhD grant from the French ‘Ministère de la Recherche.' The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.