Dataset Information

Gabapentin Prevents Progressive Increases in Excitatory Connectivity and Epileptogenesis Following Neocortical Trauma.

ABSTRACT: Neocortical injury initiates a cascade of events, some of which result in maladaptive epileptogenic reorganization of surviving neural circuits. Research focused on molecular and organizational changes that occur following trauma may reveal processes that underlie human post-traumatic epilepsy (PTE), a common and unfortunate consequence of traumatic brain injury. The latency between injury and development of PTE provides an opportunity for prophylactic intervention, once the key underlying mechanisms are understood. In rodent neocortex, injury to pyramidal neurons promotes axonal sprouting, resulting in increased excitatory circuitry that is one important factor promoting epileptogenesis. We used laser-scanning photostimulation of caged glutamate and whole-cell recordings in in vitro slices from injured neocortex to assess formation of new excitatory synapses, a process known to rely on astrocyte-secreted thrombospondins (TSPs), and to map the distribution of maladaptive circuit reorganization. We show that this reorganization is centered principally in layer V and associated with development of epileptiform activity. Short-term blockade of the synaptogenic effects of astrocyte-secreted TSPs with gabapentin (GBP) after injury suppresses the new excitatory connectivity and epileptogenesis for at least 2 weeks. Results reveal that aberrant circuit rewiring is progressive in vivo and provide further rationale for prophylactic anti-epileptogenic use of gabapentinoids following cortical trauma.

SUBMITTER: Takahashi DK

PROVIDER: S-EPMC6041890 | biostudies-other | 2018 Aug

REPOSITORIES: biostudies-other

ACCESS DATA

Publications

Gabapentin Prevents Progressive Increases in Excitatory Connectivity and Epileptogenesis Following Neocortical Trauma.

Takahashi D K DK Jin Sha S Prince D A DA

Cerebral cortex (New York, N.Y. : 1991) 20180801 8

Neocortical injury initiates a cascade of events, some of which result in maladaptive epileptogenic reorganization of surviving neural circuits. Research focused on molecular and organizational changes that occur following trauma may reveal processes that underlie human post-traumatic epilepsy (PTE), a common and unfortunate consequence of traumatic brain injury. The latency between injury and development of PTE provides an opportunity for prophylactic intervention, once the key underlying mecha ...[more]

PMID: 28981586

Similar Datasets

Project description:ObjectiveTissue remodeling has been described in brain circuits that are involved in the generation and propagation of epileptic seizures. Human and animal studies suggest that the anterior piriform cortex (aPC) is crucial for seizure expression in focal epilepsies. Here, we investigate the effect of kainic-acid (KA)-induced seizures on the effective connectivity of the aPC with bilateral hippocampal CA3 regions using cerebro-cerebral evoked potentials (CCEPs).MethodsAdult male Sprague-Dawley rats were implanted with a tripolar electrode in the left aPC for stimulation and recording, and with unipolar recording electrodes in bilateral CA3 regions. Single pulse stimulations were given to the aPC and CCEPs were averaged before KA injections and after the emergence of spontaneous recurrent seizures (SRS). Similar recordings at equivalent time intervals were obtained from animals that received saline injections instead of KA (controls).ResultsIn the experimental group, the percentage change of increased amplitude of the contralateral (but not ipsilateral) CA3 CCEPs between pre-KA injection and after the emergence of SRS was significantly greater than in controls. No significant single-pulse-induced spectral change responses were observed in either epileptic or control rats when comparing pre- and post-stimulus time intervals. Also, we found no correlation between seizure frequency and the extent of amplitude changes in the CCEPs.ConclusionsIn the KA model, epileptogenesis results in plastic changes that manifest as an amplification of evoked potential amplitudes recorded in the contralateral hippocampus in response to single-pulse stimulation of the aPC. These results suggest epileptogenesis-induced facilitation of interhemispheric connectivity between the aPC and the hippocampus. Since the amplitude increase of the contralateral CCEP is a possible in vivo biomarker of epilepsy, any intervention (e.g. neuromodulatory) that can reverse this phenomenon may hold a potential antiepileptic efficacy.

Project description:Electrophysiological experiments in the partial cortical isolation ("undercut" or "UC") model of injury-induced neocortical epileptogenesis have shown alterations in GABAergic synaptic transmission attributable to abnormalities in presynaptic terminals. To determine whether the decreased inhibition was associated with structural abnormalities in GABAergic interneurons, we used immunocytochemical techniques, confocal microscopy and EM in UC and control sensorimotor rat cortex to analyze structural alterations in fast-spiking parvalbumin-containing interneurons and pyramidal (Pyr) cells of layer V. Principle findings were: 1) there were no decreases in counts of parvalbumin (PV)- or GABA-immunoreactive interneurons in UC cortex, however there were significant reductions in expression of VGAT and GAD-65 and -67 in halos of GABAergic terminals around Pyr somata in layer V. 2) Consistent with previous results, somatic size and density of Pyr cells was decreased in infragranular layers of UC cortex. 3) Dendrites of biocytin-filled FS interneurons were significantly decreased in volume. 4) There were decreases in the size and VGAT content of GABAergic boutons in axons of biocytin-filled FS cells in the UC, together with a decrease in colocalization with postsynaptic gephyrin, suggesting a reduction in GABAergic synapses. Quantitative EM of layer V Pyr somata confirmed the reduction in inhibitory synapses. 5) There were marked and lasting reductions in brain derived neurotrophic factor (BDNF)-IR and -mRNA in Pyr cells and decreased TrkB-IR on PV cells in UC cortex. 6) Results lead to the hypothesis that reduction in trophic support by BDNF derived from Pyr cells may contribute to the regressive changes in axonal terminals and dendrites of FS cells in the UC cortex and decreased GABAergic inhibition.SignificanceInjury to cortical structures is a major cause of epilepsy, accounting for about 20% of cases in the general population, with an incidence as high as ~50% among brain-injured personnel in wartime. Loss of GABAergic inhibitory interneurons is a significant pathophysiological factor associated with epileptogenesis following brain trauma and other etiologies. Results of these experiments show that the largest population of cortical interneurons, the parvalbumin-containing fast-spiking (FS) interneurons, are preserved in the partial neocortical isolation model of partial epilepsy. However, axonal terminals of these cells are structurally abnormal, have decreased content of GABA synthetic enzymes and vesicular GABA transporter and make fewer synapses onto pyramidal neurons. These structural abnormalities underlie defects in GABAergic neurotransmission that are a key pathophysiological factor in epileptogenesis found in electrophysiological experiments. BDNF, and its TrkB receptor, key factors for maintenance of interneurons and pyramidal neurons, are decreased in the injured cortex. Results suggest that supplying BDNF to the injured epileptogenic brain may reverse the structural and functional abnormalities in the parvalbumin FS interneurons and provide an antiepileptogenic therapy.

Dataset Information

Gabapentin Prevents Progressive Increases in Excitatory Connectivity and Epileptogenesis Following Neocortical Trauma.

Publications

Gabapentin Prevents Progressive Increases in Excitatory Connectivity and Epileptogenesis Following Neocortical Trauma.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets