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.

Traumatic Brain Injury Induces Rapid Enhancement of Cortical Excitability in Juvenile Rats

“…However, during recording, we observed distinct spontaneous synaptic burst discharges that resembled the epileptiform activity observed in vivo . Based on previous reports [55], detection of synaptic bursts was determined by the presence of a minimum of three simultaneous sEPSCs within 250 mseconds that did not return to baseline. Synaptic bursts were then detected over a 5-min period of sEPSC recording from control or CCI animals.…”

Prolonged ampakine exposure prunes dendritic spines and increases presynaptic release probability for enhanced long‐term potentiation in the hippocampus

“…The culture medium consisted of 25% heat‐inactivated horse serum, 25% Hank's balanced salt solution, and 50% Basal medium Eagle. Slice cultures were maintained in the incubator with a roller‐drum for 3 weeks before experimentation to allow for maturation (Gill et al ., ). The spine distribution is not different in cultures maintained for 3–6 weeks (Chang et al ., ).…”

Dynorphin up-regulation in the dentate granule cell mossy fiber pathway following chronic inhibition of GluN2B-containing NMDAR is associated with increased CREB (Ser 133) phosphorylation, but is independent of BDNF/TrkB signaling pathways

“…Vehicle- and drug-treated cultures were always studied concurrently under identical experimental conditions. In experiments examining the effects of TrkB activation on dynorphin expression cultures also were treated for the full 17-21 day culture period with the TrkB-human IgG-Fc chimera, TrkB-Fc (2 μg/mL; R&D Systems, Minneapolis, MD; Rex et al, 2006; Rex et al, 2007; Xapelli et al, 2008; Lauterborn et al, 2009; Aguirre and Baudry 2009; Gill et al, 2013) diluted in medium, the tyrosine kinase inhibitor K252a (200 nM; EMD Chemicals, Gibbstown, NJ; Tyler and Pozzo-Miller 2001; Koyama rt al., 2004; Pozzo-Miller 2006; Sato et al, 2007) prepared in 0.02% DMSO, or their respective controls human IgG-Fc (2 μg/mL; R&D Systems, Minneapolis, MD) or 0.02% DMSO (Sigma, St. Louis, MO) diluted in medium. Only those hippocampal slice cultures exhibiting distinctive cell layers at the end of the 17-21 day culture period were used in subsequent experiments.…”