Critical role of trkB receptors in reactive axonal sprouting and hyperexcitability after axonal injury

Abstract

Aungst S, England PM, Thompson SM. Critical role of trkB receptors in reactive axonal sprouting and hyperexcitability after axonal injury. J Neurophysiol 109: 813-824, 2013. First published November 14, 2012 doi:10.1152/jn.00869.2012.-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 injuryinduced processes are critical. We tested the hypothesis that trkB activation promotes delayed injury-induced hyperexcitability in part by promoting reactive axonal sprouting. We modeled penetrative TBI with transection of the Schaffer collateral pathway in knock-in mice having an introduced mutation in the trkB receptor (trkB F616A ) that renders it susceptible to inhibition by the novel small molecule 1NMPP1. We observed that trkB activation was increased in area CA3 1 day after injury and that expression of a marker of axonal growth, GAP43, was increased 7 days after lesion. Extracellular field potentials in stratum pyramidale of area CA3 in acute slices from sham-operated 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 after lesion in untreated mice but not in mice treated with 1NMPP1. We 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. traumatic brain injury; hippocampus; lesion; plasticity; posttraumatic epilepsy TRAUMATIC BRAIN INJURY (TBI) causes devastating cognitive, sensory, emotional, and motor deficits in millions of patients.

Integrins promote axonal regeneration after injury of the nervous system

“…However, as elaborated above for integrin receptors, additional interventions would be required to enhance the transport of TrkB into the corticospinal tract to promote substantial regeneration after spinal cord injury. In addition, it had been shown in hippocampal slice cultures that the activation state of TrkB correlates with axonal sprouting (Aungst, England & Thompson, ). The activation state of Trk receptors may therefore influence the regeneration response as well.…”

Blocking brain‐derived neurotrophic factor inhibits injury‐induced hyperexcitability of hippocampal CA3 neurons

“…We found that chronically treated TrkB‐Fc slices had fewer spontaneous APs than untreated lesioned slices. Moreover, Schaffer collateral lesion caused an increase in compound fEPSPs in area CA3, consistent with epileptiform activity and hyperexcitability, similarly to in vivo Schaffer collateral lesion (Aungst et al ., ). This change in network activity was also attenuated with TrkB‐Fc treatment.…”

“…This may have implications for post-traumatic epilepsy, as recurrent epileptic seizures are a common clinical consequence of trau-matic brain injury (Annegers et al, 1998). Others have shown that Schaffer collateral lesion can result in increased network activity after the addition of a mildly proconvulsive amount of bicuculline (0.1 lM), a GABA A receptor antagonist (Aungst et al, 2013). Moreover, evidence from in vivo models of epilepsy has shown that axonal sprouting can occur in the hippocampus after induction of status epilepticus with convulsants.…”

“…This resulted in more reciprocal excitatory synaptic connections between CA3 cells, and led to hyperexcitability of CA3 neurons 14 days following transection . Recent evidence has demonstrated that BDNF expression and TrkB expression are upregulated 72 h after Schaffer collateral injury (Dinocourt et al, 2006;Aungst et al, 2013). Moreover, conditional partial knockdown of the BDNF receptor, TrkB, can reduce CA3 axonal sprouting after Schaffer collateral lesion (Dinocourt et al, 2006).…”

Long Term Effects of Early Life Maternal Separation During Tyrosine Receptor Kinase B (TrkB) Knockdown

“…Nineteen studies to date have utilized the TrkB F616A mutants for analysis of TrkB signalling in studies on nociception (Renn et al, 2009;Wang et al, 2009), neuromuscular function (Greising et al, 2015), hypothalamic function (Bariohay et al, 2009;Byerly et al, 2013), inhibitory circuity maturation (Vandenberg et al, 2015), spinal cord injury (Zhan et al, 2013;Mantilla et al, 2014), traumatic brain injury (Aungst et al, 2013), motivated behaviour (Johnson et al, 2008), antidepressant drug signalling (Rantamäki et al, 2011), circadian rhythms (Girardet et al, 2013), retinal circuitry (Kaneko et al, 2008;Majumdar et al, 2011), tests of TrkB agonists (Jang et al, 2010;Choi et al, 2012), receptor sequestration (Mou et al, 2011), glucocorticoid receptor interaction (Arango-Lievano et al, 2015, and most recently, the interaction of RhoGTPase signalling (Hedrick et al, 2016). This body of research demonstrates that this transgenic line of mice is a valuable model for analyzing the influence of TrkB.FL receptor function.…”