BDNF reduces miniature inhibitory postsynaptic currents by rapid downregulation of GABA(A) receptor surface expression.
Changes in neurotransmitter receptor density at the synapse have been proposed as a mechanism underlying synaptic plasticity. Neurotrophic factors are known to influence synaptic strength rapidly. In the present study, we found that brain-derived neurotrophic factor (BDNF) acts postsynaptically to reduce gamma-aminobutyric acid (GABA)-ergic function. Using primary cultures of rat hippocampal neurons, we investigated the effects of BDNF on GABAergic miniature inhibitory postsynaptic currents (mIPSCs) and on the localization of GABAA receptors. Application of BDNF (100 ng/mL) led within minutes to a marked reduction (33.5%) of mIPSC amplitudes in 50% of neurons, recorded in the whole-cell patch-clamp mode, leaving frequency and decay kinetics unaffected. This effect was blocked by the protein kinase inhibitor K252a, which binds with high affinity to trkB receptors. Immunofluorescence staining with an antibody against trkB revealed that about 70% of cultured hippocampal pyramidal cells express trkB. In dual labelling experiments, use of neurobiotin injections to label the recorded cells revealed that all cells responsive to BDNF were immunopositive for trkB. Treatment of cultures with BDNF reduced the immunoreactivity for the GABAA receptor subunits-alpha2, -beta2,3 and -gamma2 in the majority of neurons. This effect was detectable after 15 min and lasted at least 12 h. Neurotrophin-4 (NT-4), but not neurotrophin-3 (NT-3), also reduced GABAA receptor immunoreactivity, supporting the proposal that this effect is mediated by trkB. Altogether the results suggest that exposure to BDNF induces a rapid reduction in postsynaptic GABAA receptor number that is responsible for the decline in GABAergic mIPSC amplitudes.
Brünig
I
I
Institute of Pharmacology and Toxicology, University of Zurich, Winterthurerstr. 190, 8057 Zurich, Switzerland.
Penschuck
S
S
Berninger
B
B
Benson
J
J
Fritschy
J M
JM
D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000494:pharmacology*; D002478:Cells, Cultured; D015536:Down-Regulation / Q000187:drug effects / Q000502:physiology; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000502:physiology*; D005260:Female; D005333:Fetus / Q000166:cytology; D006624:Hippocampus / Q000166:cytology; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D009433:Neural Inhibition / Q000187:drug effects / Q000502:physiology; D018408:Patch-Clamp Techniques; D011247:Pregnancy; D017966:Pyramidal Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D051381:Rats; D020813:Receptor, trkB / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000378:metabolism; D011963:Receptors, GABA-A / Q000378:metabolism*
D019208:Brain-Derived Neurotrophic Factor; D011956:Receptors, Cell Surface; D011963:Receptors, GABA-A; D020813:Receptor, trkB