The Role of Homeostatic Plasticity in Post-Traumatic Epilepsy

Abstract

Traumatic brain injury (TBI) can cause post-traumatic epilepsy (PTE), a condition characterized by chronic spontaneous seizures via aberrant hyperexcitability. Homeostatic plasticity is a phenomenon in which neurons adjust their neurotransmission in response to an imposed decrease or increase in activity to maintain a stable level of firing. It is possible that a compensatory response to TBI-induced loss of activity may lead to pathological hyperexcitability that results in PTE. We hypothesized that enhancing activity after TBI could treat PTE by suppressing the putative compensatory response. Using a neocortical (undercut) model of PTE, we tested the hypotheses that homeostatic plasticity contributes to PTE and that enhancing neuronal activity will mitigate PTE. Two sets of experiments were conducted. First, cortical pyramidal neuron activity was imaged in adult Thy1-GCaMP6 transgenic mice with undercut injury using in vivo two-photon microscopy multiple times for four weeks. Frequency of calcium transients of individual neurons was analyzed with a custom Matlab script (developed by A. Moore) and ImageJ. Graph theory metrics were applied to correlated time course data to quantify changes in network metrics over time and between the undercut and sham surgery mice. Second, to determine the effect of activity enhancement on PTE, undercut Thy1-Channelrhodopsin 2 transgenic mice were assigned to one of three conditions: no treatment, daily intraperitoneal injection of D-cycloserine (DCS), or optogenetic stimulation for 10 days. Post-treatment, continuous wireless electroencephalography (EEG) recordings monitored spontaneous seizure activity for two weeks. Seizure susceptibility was measured using the pentylenetetrazol (PTZ) test. Seizure frequency was determined manually after applying standard signal processing methods. The feasibility of machine learning algorithms to identify seizures was explored. The project underscores the need for modern standardized and objective analyses of PTE in rodent models. Our data suggest that local connectivity in layers II/III pyramidal neurons exhibits small world network architecture during the latent period (weeks 1-4 after undercut injury) and that enhancing cortical activity with DCS or LED 4-6 weeks after undercut injury can reduce spontaneous seizure behaviors and paroxysmal EEG features associated with different seizure types. This work provides the foundation for future therapies for PTE that activate excitatory cortical neurons.