Dampened hippocampal oscillations and enhanced spindle activity in an asymptomatic model of developmental cortical malformations.
Developmental cortical malformations comprise a large spectrum of histopathological brain abnormalities and syndromes. Their genetic, developmental and clinical complexity suggests they should be better understood in terms of the complementary action of independently timed perturbations (i.e., the multiple-hit hypothesis). However, understanding the underlying biological processes remains puzzling. Here we induced developmental cortical malformations in offspring, after intraventricular injection of methylazoxymethanol (MAM) in utero in mice. We combined extensive histological and electrophysiological studies to characterize the model. We found that MAM injections at E14 and E15 induced a range of cortical and hippocampal malformations resembling histological alterations of specific genetic mutations and transplacental mitotoxic agent injections. However, in contrast to most of these models, intraventricularly MAM-injected mice remained asymptomatic and showed no clear epilepsy-related phenotype as tested in long-term chronic recordings and with pharmacological manipulations. Instead, they exhibited a non-specific reduction of hippocampal-related brain oscillations (mostly in CA1); including theta, gamma and HFOs; and enhanced thalamocortical spindle activity during non-REM sleep. These data suggest that developmental cortical malformations do not necessarily correlate with epileptiform activity. We propose that the intraventricular in utero MAM approach exhibiting a range of rhythmopathies is a suitable model for multiple-hit studies of associated neurological disorders.
Laboratorio de Circuitos Neuronales, Instituto Cajal, CSIC Madrid, Spain.
Elena
E
Cid
Laboratorio de Circuitos Neuronales, Instituto Cajal, CSIC Madrid, Spain.
Daniel
D
Gomez-Dominguez
Laboratorio de Circuitos Neuronales, Instituto Cajal, CSIC Madrid, Spain ; Servicio de Neurofisiologia Clínica, Hospital General Universitario Gregorio Marañón Madrid, Spain.
David
D
Martin-Lopez
Laboratorio de Circuitos Neuronales, Instituto Cajal, CSIC Madrid, Spain ; Universidad Europea de Madrid, Ciencias Biomédicas Básicas Madrid, Spain.
Beatriz
B
Gal
Laboratorio de Circuitos Neuronales, Instituto Cajal, CSIC Madrid, Spain.
François
F
Laurent
Servicio de Neurobiología, Instituto Ramón y Cajal de Investigación Sanitaria Madrid, Spain.
Jose M
JM
Ibarz
Institut du Fer à Moulin Paris, France ; Sorbonne Universités, Université Pierre et Marie Curie Paris, France ; Institut National de la Santé et de la Recherche Médicale UMRS 839 Paris, France.
Fiona
F
Francis
Laboratorio de Circuitos Neuronales, Instituto Cajal, CSIC Madrid, Spain.
Liset
L
Menendez de la Prida
epilepsy; hippocampal heterotopia; multi-site recordings; oscillations