Brain-derived neurotrophic factor-dependent unmasking of “silent” synapses in the developing mouse barrel cortex

Abstract

Brain-derived neurotrophic factor (BDNF) is a critical modulator of central synaptic functions such as long-term potentiation in the hippocampal and visual cortex. Little is known, however, about its role in the development of excitatory glutamatergic synapses in vivo. We investigated the development of N-methyl-D-aspartate (NMDA) receptor (NMDAR)-only synapses (silent synapses) and found that silent synapses were prominent in acute thalamocortical brain slices from BDNF knockout mice even after the critical period. These synapses could be partially converted to ␣-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR)-containing ones by adding back BDNF alone to the slice or fully converted to together with electric stimulation without affecting NMDAR transmission. Electric stimulation alone was ineffective under the BDNF knockout background. Postsynaptically applied TrkB kinase inhibitor or calcium-chelating reagent blocked this conversion. Furthermore, the AMPAR C-terminal peptides essential for interaction with PDZ proteins postsynaptically prevented the unmasking of silent synapses. These results suggest that endogenous BDNF and neuronal activity synergistically activate AMPAR trafficking into synaptic sites.

Developmental synaptic plasticity at the thalamocortical input to barrel cortex: Mechanisms and roles

“…Barrel formation, however, is unaffected in the BDNF knock-out although ultra-structural studies show that whisker stimulation does not result in new synapse formation that occurs in wild-type animals (Genoud et al, 2004). Consistent with this, BDNF knock-out mice have a higher proportion of silent synapses at TC inputs than do wild types, and an LTP pairing protocol will not cause unsilencing in these knock outs unless BDNF is exogenously applied at the same time (Itami et al, 2003). Moreover, unsilencing of silent synapses during LTP is prevented by inhibition of the TrkB tyrosine kinase activity, the receptor for BDNF.…”

Endogenous Brain-Derived Neurotrophic Factor Triggers Fast Calcium Transients at Synapses in Developing Dendrites

“…This observation implicates intrinsic BDNF signaling in regulating the development of single synapses, possibly by mediating synaptic maturation (Fig. 3) (Rutherford et al, 1998;Itami et al, 2003;Walz et al, 2006). In addition, because TrkB activates diverse intracellular signaling pathways, the intriguing possibility arises that BDNF-TrkB signaling activates parallel pathways to regulate local and global as well as rapid and slower aspects of neuronal development differentially.…”

Spinal Synaptic Enhancement with Acute Intermittent Hypoxia Improves Respiratory Function after Chronic Cervical Spinal Cord Injury

“…Transformation of silent to effective synaptic pathways by serotonin and BDNF has been described in the spinal dorsal horn (Itami et al, 2003;Kim et al, 2003). Presynaptically, serotonin induces synaptic vesicle filling of preexisting empty varicosities and permits growth of new functional varicosities (Kim et al, 2003).…”

“…Presynaptically, serotonin induces synaptic vesicle filling of preexisting empty varicosities and permits growth of new functional varicosities (Kim et al, 2003). Postsynaptically, BDNF and serotonin can strengthen silent synapses by increased insertion of cytosolic AMPA receptors in the postsynaptic membrane (Zhuo, 2000;Itami et al, 2003). Given the serotonin dependence of pLTF, the inability to elicit pLTF 2 weeks after C2 spinal hemisection is predictable, because descending ipsilateral projections from brainstem serotonergic neurons are essentially disrupted.…”