Browsing School of Medicine by Author "Aungst, Stephanie"
Critical role of trkB receptors in reactive axonal sprouting and hyperexcitability after axonal injuryAungst, Stephanie; Thompson, Scott M., Ph.D. (2012)Traumatic brain injury (TBI) causes many long-term neurological complications. Some of these conditions, such as posttraumatic epilepsy, are characterized by increased excitability that typically arises after a latent period lasting from months to years, suggesting that slow injury-induced processes are critical. I tested the hypothesis that trkB activation promotes delayed injury-induced hyperexcitability in the hippocampus by promoting reactive axonal sprouting. I modeled penetrative TBI with transection of a major excitatory axonal system, the Schaffer collateral pathway in knock-in mice having an introduced mutation in the trkB receptor (trkBF616A) that renders it susceptible to inhibition by the small, synthetic molecule 1NMPP1. I observed that trkB activation was increased in area CA3 one day after injury and that expression of a marker of axonal growth, GAP43, was increased seven days postlesion. Extracellular field potentials in stratum pyramidale of area CA3 in acute slices from sham and lesioned mice were normal in control saline. Abnormal bursts of population spikes were observed under conditions that were mildly proconvulsive, but only in slices taken from mice lesioned 7-21 days earlier and not in slices from control mice. trkB activation, GAP43 upregulation, and hyperexcitability were diminished by systemic administration of 1NMPP1 for 7 days after the lesion. Synaptic transmission from area CA3 to area CA1 recovered 7 days postlesion in untreated mice, but not in mice treated with 1NMPP1. I conclude that trkB receptor activation and reactive axonal sprouting are critical factors in injury-induced hyperexcitability and may contribute to the neurological complications of TBI.