title: Blocking brain-derived neurotrophic factor inhibits injury-induced hyperexcitability of hippocampal CA3 neurons.
abstract: Brain trauma can disrupt synaptic connections, and this in turn can prompt axons to sprout and form new connections. If these new axonal connections are aberrant, hyperexcitability can result. It has been shown that ablating tropomyosin-related kinase B (TrkB), a receptor for brain-derived neurotrophic factor (BDNF), can reduce axonal sprouting after hippocampal injury. However, it is unknown whether inhibiting BDNF-mediated axonal sprouting will reduce hyperexcitability. Given this, our purpose here was to determine whether pharmacologically blocking BDNF inhibits hyperexcitability after injury-induced axonal sprouting in the hippocampus. To induce injury, we made Schaffer collateral lesions in organotypic hippocampal slice cultures. As reported by others, we observed a 50% reduction in axonal sprouting in cultures treated with a BDNF blocker (TrkB-Fc) 14 days after injury. Furthermore, lesioned cultures treated with TrkB-Fc were less hyperexcitable than lesioned untreated cultures. Using electrophysiology, we observed a two-fold decrease in the number of CA3 neurons that showed bursting responses after lesion with TrkB-Fc treatment, whereas we found no change in intrinsic neuronal firing properties. Finally, evoked field excitatory postsynaptic potential recordings indicated an increase in network activity within area CA3 after lesion, which was prevented with chronic TrkB-Fc treatment. Taken together, our results demonstrate that blocking BDNF attenuates injury-induced hyperexcitability of hippocampal CA3 neurons. Axonal sprouting has been found in patients with post-traumatic epilepsy. Therefore, our data suggest that blocking the BDNF-TrkB signaling cascade shortly after injury may be a potential therapeutic target for the treatment of post-traumatic epilepsy.
authors.affiliation: Department of Pharmacology & Therapeutics, McGill University, Bellini Life Sciences Complex, 3649 Promenade Sir William Osler, Montreal, QC, Canada, H3G 0B1.
authors.forename: Raminder
authors.initials: R
authors.lastname: Gill
authors.forename: Philip K-Y
authors.initials: PK
authors.lastname: Chang
authors.forename: George A
authors.initials: GA
authors.lastname: Prenosil
authors.forename: Emily C
authors.initials: EC
authors.lastname: Deane
authors.forename: Rebecca A
authors.initials: RA
authors.lastname: McKinney
mesh_terms: D000818:Animals; D001369:Axons / Q000473:pathology; D001930:Brain Injuries / Q000378:metabolism / Q000503:physiopathology*; D019208:Brain-Derived Neurotrophic Factor / Q000172:deficiency*; D056654:CA3 Region, Hippocampal / Q000378:metabolism / Q000473:pathology / Q000502:physiology*; D019706:Excitatory Postsynaptic Potentials; D008562:Membrane Glycoproteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D017966:Pyramidal Cells / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D020813:Receptor, trkB
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D008562:Membrane Glycoproteins; D011505:Protein-Tyrosine Kinases; C064371:Ntrk2 protein, mouse; D020813:Receptor, trkB
keywords: GAP43; axonal sprouting; brain-derived neurotrophic factor; organotypic hippocampal slices; post-traumatic epilepsy