Direct and Collateral Alterations of Functional Cortical Circuits in a Rat Model of Subcortical Band Heterotopia.

Vanessa Plantier,Ingrid Bureau,Fanny Sandrine Martineau,Surajit Sahu,Emmanuelle Buhler,Jean-Bernard Manent,Alfonso Represa,Françoise Watrin

doi:10.1093/cercor/bhy307

Abstract

Subcortical band heterotopia (SBH), also known as double-cortex syndrome, is a neuronal migration disorder characterized by an accumulation of neurons in a heterotopic band below the normotopic cortex. The majority of patients with SBH have mild to moderate intellectual disability and intractable epilepsy. However, it is still not clear how cortical networks are organized in SBH patients and how this abnormal organization contributes to improper brain function. In this study, cortical networks were investigated in the barrel cortex in an animal model of SBH induced by in utero knockdown of Dcx, main causative gene of this condition in human patients. When the SBH was localized below the Barrel Field (BF), layer (L) four projection to correctly positioned L2/3 pyramidal cells was weakened due to lower connectivity. Conversely, when the SBH was below an adjacent cortical region, the excitatory L4 to L2/3 projection was stronger due to increased L4 neuron excitability, synaptic strength and excitation/inhibition ratio of L4 to L2/3 connection. We propose that these developmental alterations contribute to the spectrum of clinical dysfunctions reported in patients with SBH.

Highlights

Gray matter heterotopia (GMH) is a group of neurological disorders resulting from abnormal neuronal migration or abnormal positioning and proliferation of neural progenitors
Visual inspection of slices revealed that Subcortical band heterotopia (SBH) position in the white matter varied from below the Barrel Field (BF) to below the adjacent motor areas (Fig. 1), likely depending on the position of electrodes used for electroporating RNAi constructs
We took advantage of this inter-individual difference to evaluate separately the effects of SBH on circuit organization of functional connections impinging onto pyramidal cells that were correctly positioned in L2/3 of the BF

Summary

Introduction

Gray matter heterotopia (GMH) is a group of neurological disorders resulting from abnormal neuronal migration or abnormal positioning and proliferation of neural progenitors (reviewed in Watrin et al 2015). Functional imaging investigations performed on a restricted number of patients suggest that GMHs are associated with reorganizations of cortical representations (Richardson et al 1998; Pinard et al 2000; Spreer et al 2001; Jirsch et al 2006; Vitali et al 2008). These authors reported a more widespread activation of the normotopic cortex as compared with control subjects and even in some patients the recruitment of the cortex beyond the limits of the 2 | Cerebral Cortex

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