Epilepsy, Language and Development : molecular networks, pathophysiology and cortical development – EPILAND

Genetic studies of patients with epilepsy and comorbid manifestations (language impairment, migraine, autism, etc) lead to the identification of specific causes, which represent as many key starting points to understand those pathologies and their associations. Complementary methods (molecular biology, biochemistry, design of rodent models of altered brain development - notably via in utero RNA silencing or by viral (CMV) infection) and the analyzes of long-term, postnatal consequences of such prenatal defects, will help in understanding the pathological mechanisms and the underlying developmental processes. Those animal models will also lead to the design of novel therapeutic and preventive strategies against the long-term consequences.

Identification of the gene (PRRT2) responsible for the variable association of infantile convulsions, unvoluntary abnormal movements, and hemiplegic migraine.
Identification of genomic alterations that strongly indicate genetic influence in epileptic encephalopathies of the Landau-Kleffner type, and that make the link with the spectrum of autism disorders.
Creation of a rat model of altered development of the cerebral cortex by in utero Srpx2 knock-down, with postnatal epileptiform consequences.
Demonstration that Srpx2 influences neuronal migration and alpha-tubulin acetylation.
Efficient rescue of impaired neuronal migration by pharmacological treatment of organotypic slices in vitro: a first stage towards possible early prevention in vivo.

Future identification of genetic bases for epileptic encephalopathies of the Landau-Kleffner type: pathophysiological pathways, pharmacological targets, genetic counseling, diagnosis.
Early origin of postnatal cerebral disorders: towards the definition of a developmental therapeutic window to prevent the early alterations of brain development.

A unique mutation in the PRRT2 gene causes either of infantile convulsions, paroxysmal dyskinesia, or migraine, variably associated. Two articles (one published, one in press) report on these findings, also cited in one related editorial to be published in Neurology. Already more than 25 independent articles confirm our data.
The pathophysiology of the Landau-Kleffner syndrome (LKS, acquired epileptic aphasia) has remained unknown since decades. Our data provide the first evidence for possible genetic origin, by identifying potentially pathogenic genomic alterations that in addition can also be found in autistic patients. Toese data that we published recently, are currently being extended in order to confirm the involvement of specific genetic defects. This represents the first insights ever into the possible mechanisms of LKS, which is at the crossraods between epilepsy, autism, language disorders, and cognitive issues.
The efficient correction of abnormal neuronal migration in vitro that we have obtained recently, opens promising avenues towards the possible prevention of long-term consequences of such developmental defects in vivo, which we are currently testing by in utero pharmacological treatment in the appropriate animal model.

Language disorders and focal epilepsy are common neurological disorders with major medical, educational and socio-economical disturbances. Moreover, how the language cortex develops and functions represents a crucial scientific issue. Our project aims at understanding the various and related developmental disorders of the speech cortex and circuits, at bridging clinical, genetic, molecular, functional and electrophysiological gaps between such disorders, and at modifying the brain developmental programs the corresponding proteins are involved in.
While progress in the analysis of the speech networks has been made through neuroimaging, little is known at the molecular level. We and others have identified a few genes and pathways in the recent years and our most recent and unpublished data demonstrate the existence of a FOXP2-SRPX2/uPAR regulatory link that is altered in speech disorder, and a role for rat Srpx2 (Sushi-Repeat Protein) in neuronal migration during brain cortical development. These data represent key entries to address several crucial scientific issues: i/further identify and study the molecular pathways for the spectrum of brain disorders variably associating focal epilepsy, speech impairment, and altered development of the speech areas and networks : rolandic epilepsy, verbal dyspraxia, continuous spike-wave during slow sleep syndrome, perisylvian polymicrogyria,…; ii/make links between such phenotypes without any detectable brain anomaly and those with developmental defects, by studying the involvement of molecular pathways such as Srpx2 in brain cortical development; iii/study the generation of neuronal networks in the context of in utero alteration of this pathway; iv/test the possibility of rescuing the phenotype of impaired neuronal migration after birth in a conditional way; v/appreciate the influence of nongenetic factors such as drugs and viruses, on the phenotypes created by genetic alteration of this pathway.
A highly complementary combination of advances in genomics, molecular and cell biology, neurobiology, and neurophysiology must be employed by several partners with specific expertises. The project is organized in several tasks that each will address specific issues. We will: study the clinical, genetic and genomic overlaps between various disorders of the speech areas and networks; identify regulatory and functional molecular links between the above related disorders; decipher the role of Srpx2 in the development of the rat brain cortex by RNA interference in utero, determine how do the SRPX2 mutations interfere with the regular pattern of neuronal migration, and test whether the phenotype can be rescued by conditional expression of Srpx2 after birth; investigate for any early alteration in the cortical neuronal functioning and network organization caused by Srpx2 silencing in utero and dissect the mechanisms underlying the generation of aberrant patterns by misplaced neurons; address the general question of the possible influence and/or use of environmental factors (drugs, viruses) during pregnancy on the neuronal migration defects of genetic origin.
Starting from previous data that constitute crucial key points, we expect our results to be important in the fields of those epilepsies with language deficits and of the speech disorders, and of the anomalies of cortical development. The way aberrant networks are generated by misplaced neurons is also a crucial and fundamental issue. Generally testing the influence of non-genetic (environmental) factors such as drugs and viruses on the in utero phenotypes obtained by alteration of a given gene (here, Srpx2) will also represent an important key step towards a better understanding on the respective relationship between environmental and genetic factors during pregnancy. Finally, conditional rescue by Srpx2, a secreted protein, will provide a proof-of-concept towards the future design of specific therapeutic strategies.