Calcium and free radicals: Mediators of neurotrophic factor and excitatory transmitter-regulated developmental plasticity and cell death

Mark P. Mattson

Research output: Contribution to journalArticlepeer-review

61 Scopus citations


An intricate interplay between neurotrophic factor and excitatory transmitter signaling systems exists in both the developing and adult brain. Interactions between these signaling systems appears to be a fundamental mechanism regulating adaptive neuritic pruning and cell death. Accordingly, genetically and environmentally induced imbalances in this regulatory system are implicated in the pathogenesis of a variety of acute (such as stroke and traumatic brain injury) and chronic (such as Alzheimer's and Parkinson's diseases) neurodegenerative disorders. Neurons exhibit both acute and delayed responses to neurotrophic factors and excitatory transmitters; acute responses include rapid structural remodeling of growth cones and synaptic contacts, and delayed responses include induction or suppression of the expression of gene products involved in neuroprotection. Intracellular free Ca2+ and free radicals appear to play key roles as mediators of both acute and delayed responses of neurons to excitatory transmitters and neurotrophic factors. For example, the delayed response to bFGF includes stabilization of Ca2+ homeostasis and induction of antioxidant enzymes; both of these actions of bFGF antagonize the dendrite outgrowth-stabilizing and excitotoxic actions of glutamate. Intricate regulatory interactions exist between glutamate and neurotrophic factor signaling systems so that glutamate can induce the expression of neurotrophic factors and their receptors, and neurotrophic factors modulate the expression of exitatory transmitter receptors. A novel signaling system that can interact with both glutamate and neurotrophic factor systems is that of the β-amyloid precursor protein, which appears to play important roles in neuronal plasticity and survival. A working model for the regulation of neuronal survival and connectivity is presented, which considers spatial and temporal constraints on release of, and receptors for, neurotrophic factors and excitatory transmitters.

Original languageEnglish (US)
Pages (from-to)79-91
Number of pages13
JournalPerspectives on Developmental Neurobiology
Issue number2
StatePublished - 1996
Externally publishedYes


  • Amyloid precursor protein
  • Antioxidant
  • Fibroblast growth factor
  • Glutamate
  • Growth cone
  • Nerve growth factor
  • Protein kinase
  • Reactive oxygen species

ASJC Scopus subject areas

  • Neuroscience(all)
  • Developmental Biology


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