Partial TrkB receptor activation suppresses cortical epileptogenesis through actions on parvalbumin interneurons

Abstract

Post-traumatic epilepsy is one of the most common and difficult to treat forms of acquired epilepsy worldwide. Currently, there is no effective way to prevent post-traumatic epileptogenesis. It is known that abnormalities of interneurons, particularly parvalbumin-containing interneurons, play a critical role in epileptogenesis following traumatic brain injury. Thus, enhancing the function of existing parvalbumin interneurons might provide a logical therapeutic approach to prevention of post-traumatic epilepsy. The known positive effects of brain-derived neurotrophic factor on interneuronal growth and function through activation of its receptor tropomyosin receptor kinase B, and its decrease after traumatic brain injury, led us to hypothesize that enhancing trophic support might improve parvalbumin interneuronal function and decrease epileptogenesis. To test this hypothesis, we used the partial neocortical isolation ('undercut', UC) model of posttraumatic epileptogenesis in mature rats that were treated for 2 weeks, beginning on the day of injury, with LM22A-4, a newly designed partial agonist at the tropomyosin receptor kinase B. Effects of treatment were assessed with Western blots to measure pAKT/AKT; immunocytochemistry and whole cell patch clamp recordings to examine functional and structural properties of GABAergic interneurons; field potential recordings of epileptiform discharges in vitro; and video-EEG recordings of PTZ-induced seizures in vivo. Results showed that LM22A-4 treatment 1) increased pyramidal cell perisomatic immunoreactivity for VGAT, GAD65 and parvalbumin; 2) increased the density of close appositions of VGAT/gephyrin immunoreactive puncta (putative inhibitory synapses) on pyramidal cell somata; 3) increased the frequency of mIPSCs in pyramidal cells; and 4) decreased the incidence of spontaneous and evoked epileptiform discharges in vitro. 5) Treatment of rats with PTX BD4-3, another partial TrkB receptor agonist, reduced the incidence of bicuculline-induced ictal episodes in vitro and PTZ induced electrographic and behavioral ictal episodes in vivo. 6) Inactivation of TrkB receptors in undercut TrkB mice with 1NMPP1 abolished both LM22A-4-induced effects on mIPSCs and on increased perisomatic VGAT-IR. Results indicate that chronic activation of the tropomyosin receptor kinase B by a partial agonist after cortical injury can enhance structural and functional measures of GABAergic inhibition and suppress posttraumatic epileptogenesis. Although the full agonist effects of brain-derived neurotrophic factor and tropomyosin receptor kinase B activation in epilepsy models have been controversial, the present results indicate that such trophic activation by a partial agonist may potentially serve as an effective therapeutic option for prophylactic treatment of posttraumatic epileptogenesis, and treatment of other neurological and psychiatric disorders whose pathogenesis involves impaired parvalbumin interneuronal function.

Partial Activation of TrkB Receptors Corrects Interneuronal Calcium Channel Dysfunction and Reduces Epileptogenic Activity in Neocortex following Injury

“…3 I ), suggesting that BD treatment increased GABA Pr. Increases in eIPSC amplitudes ( Fig 3 G vs. Fig 3 H ) were also present in slices from BD- vs. saline-treated UC rats, confirming results obtained with LM22A-4, another small molecule selective TrkB partial agonist ( Gu et al. 2018 ).…”

“…4 D – I ). In the absence of effects of TrkB activation to increase excitatory transmission and epileptogenesis in the UC model ( Gu et al. 2018 and Fig.…”

“…1995 ) ( Li and Prince 2002 ) and decreases in GABAergic transmission due to presynaptic abnormalities in interneurons ( Ma and Prince 2012 ; Gu et al. 2017 , 2018 ). We hypothesized that, by enhancing GABAergic transmission slices from UC cortex, BD treatment would reduce the capacity of the aberrant excitatory networks to generate epileptogenic events.…”

“…In neocortical layer V, there are abundant PV interneurons, while CCK cells are rare ( Uematsu et al. 2008 ), suggesting that BD upregulation of perisomatic P/Q and N channels in layer Va of injured neocortex may arise mainly from the effects of BD treatment on PV interneurons ( Gu et al. 2018 ), with less contribution from CCK interneurons.…”

TrkB agonists prevent post-ischemic BDNF-TrkB mediated emergence of refractory neonatal seizures in CD-1 pups

“…Supporting these results, the Pre LM group showed a significant increase in pERK1/2-T202/Y204 expression. Intervention with BDNF loop II mimetic LM was shown to have beneficial long-term effects in vivo, particularly in rescuing adult post-traumatic cortical epileptogenesis in a TrkB-dependent manner ( 65 ), supporting the findings reported in this study.…”