Neurosteroid-induced plasticity of immature synapses via retrograde modulation of presynaptic NMDA receptors
Journal of Neuroscience. 2005-03-02; 25(9): 2285-2294
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1. J Neurosci. 2005 Mar 2;25(9):2285-94.
Neurosteroid-induced plasticity of immature synapses via retrograde modulation of
presynaptic NMDA receptors.
Mameli M(1), Carta M, Partridge LD, Valenzuela CF.
(1)Department of Neurosciences, University of New Mexico Health Sciences Center,
Albuquerque, New Mexico 87131, USA.
Neurosteroids are produced de novo in neuronal and glial cells, which begin to
express steroidogenic enzymes early in development. Studies suggest that
neurosteroids may play important roles in neuronal circuit maturation via
autocrine and/or paracrine actions. However, the mechanism of action of these
agents is not fully understood. We report here that the excitatory neurosteroid
pregnenolone sulfate induces a long-lasting strengthening of AMPA
receptor-mediated synaptic transmission in rat hippocampal neurons during a
restricted developmental period. Using the acute hippocampal slice preparation
and patch-clamp electrophysiological techniques, we found that pregnenolone
sulfate increases the frequency of AMPA-mediated miniature excitatory
postsynaptic currents in CA1 pyramidal neurons. This effect could not be observed
in slices from rats older than postnatal day 5. The mechanism of action of
pregnenolone sulfate involved a short-term increase in the probability of
glutamate release, and this effect is likely mediated by presynaptic NMDA
receptors containing the NR2D subunit, which is transiently expressed in the
hippocampus. The increase in glutamate release triggered a long-term enhancement
of AMPA receptor function that requires activation of postsynaptic NMDA receptors
containing NR2B subunits. Importantly, synaptic strengthening could also be
triggered by postsynaptic neuron depolarization, and an anti-pregnenolone sulfate
antibody scavenger blocked this effect. This finding indicates that a
pregnenolone sulfate-like neurosteroid is a previously unrecognized retrograde
messenger that is released in an activity-dependent manner during development.
PMID: 15745954 [Indexed for MEDLINE]