Reduced Expression of Perineuronal Nets in the Tish Rat Model of Subcortical Heterotopia
Abstract number :
1.019
Submission category :
1. Basic Mechanisms / 1B. Epileptogenesis of genetic epilepsies
Year :
2018
Submission ID :
495503
Source :
www.aesnet.org
Presentation date :
12/1/2018 6:00:00 PM
Published date :
Nov 5, 2018, 18:00 PM
Authors :
Denise K. Grosenbaugh, University of Virginia and Howard P. Goodkin, University of Virginia Health System
Rationale: The tish (telencephalic internal structural heterotopia) rat arose spontaneously from a deletion of Eml1 in a colony of Sprague-Dawley (SD) rats and represents a unique animal model of a malformation of cortical development (MCD). Tish rats are characterized by a large bilateral heterotopic cortex (HCx) separated from the overlying normotopic neocortex (NNCx). A previous electrophysiological study at postnatal day (P) 15 revealed reduced GABAergic neurotransmission of layer V pyramidal cells in the NNCx, occurring prior to the onset of runs of spike wave discharges, which begin around P18 in tish rats. Perineuronal nets (PNNs) contribute to both GABAergic and glutamatergic neurotransmission, and have been implicated in neurological disorders, such as epilepsy. We hypothesized that altered PNN development in the NNCx of the young tish rat may contribute to the impaired GABAergic neurotransmission and the generation of spontaneous seizures. Methods: Immunohistochemistry was performed at P16 and P35 in control SD and tish rats using an anti-parvalbumin (PV) antibody to detect PV+ interneurons and Wisteria Floribunda Lectin (WFA) to detect PNNs. In a separate group of rats, insulin-like growth factor 1 (IGF-1; 15 mg/kg) or saline was administered daily from P3 – P35. At P36 animals were processed for immunohistochemistry to determine PNN expression. ImageJ was used to quantify the number of PNNs and the number of PV+ interneurons within somatosensory cortex 1 barrel field of the NNCx. Results: PNNs were present in the NNCx and the neocortex of both tish and control SD rats, respectively. However, the average number of WFA+ PNNs at both P16 (SD: 27.8 ± 2.4; tish: 10.9 ± 1.8, p < 0.001, n = 6) and P35 (SD: 94.6 ± 3.7; tish: 60.1 ± 1.8, p < 0.001, n = 8 – 9) was decreased in tish compared to SD rats. No difference in the number of PV+ interneurons was observed at either P16 (SD: 68.2 ± 1.8; tish: 66.2 ± 3.2, p > 0.05) or P35 (SD: 57.0 ± 3.0, tish: 52.2 ± 2.8, p > 0.05). Therefore, the average number of PV+ interneurons that co-express a WFA+ PNN is decreased in tish rats at both ages P16 (SD: 20.1 ± 1.7, tish: 8.6 ± 1, p < 0.001) and P35 (SD: 23.2 ± 2.0, tish: 16.7 ± 1.1, p < 0.05), suggesting a failure of proper PNN development in the young tish rat. Upon exogenous administration of IGF-1, there was an increase in the average number WFA+ PNNs in the NNCx (tish + IGF-1: 85.2 ± 1.4) when compared to tish rats treated with saline (tish + saline: 71.1 ± 2.1, p < 0.001, n = 7/group) during the same time period. Conclusions: These studies serve as one of the first investigations into alterations in PNN expression in a model of MCD and may shed light on their role in regulating neurotransmission in a spontaneous model of MCD and the associated epilepsy. These findings may provide a framework for continued investigation into whether IGF-1 restores GABAergic transmission and ultimately prevents the onset of spontaneous seizures in the tish rat. Funding: None