Abstract
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.
Highlights
Brain structural specificity emerges during early development through elaborated genetic programs that control cell proliferation, differentiation, migration and the formation of microcircuits in close interaction with environmental factors (Rubenstein and Rakic, 2013)
A major feature of developmental cortical malformations is the presence of microcephalia, which can be found both in patients and in animal models (Guerrini et al, 2008)
We looked at potential distortion of high-frequency oscillations (HFOs) in E14 MAM-injected mice, as HFOs are used as marker of epileptogenesis (Jefferys et al, 2012)
Summary
Brain structural specificity emerges during early development through elaborated genetic programs that control cell proliferation, differentiation, migration and the formation of microcircuits in close interaction with environmental factors (Rubenstein and Rakic, 2013). Malformations of cortical development result from disruptions in this intricate process and include a myriad of structural abnormalities. Advances of neuroimaging and genetic tools have resulted in an unprecedented profusion of information on gene mutations and structural abnormalities underlying a particular syndrome. It has become clear that mutations of a gene are not necessarily linked to a single syndrome and that clinical definition encompasses a variety of underlying biological processes. The intricacy of these syndromes reflects the complex interaction between genetic variations, de novo mutations, early brain developmental disruptions and late
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
