In different epileptic syndromes of childhood as tuberous sclerosis complex (TSC), a rare multi system genetic disease, focal cortical dysplasia type II (FCD II), and Rett syndrome, GABA shows a delay in the normal development, maintaining a less hyperpolarizing action, a typical feature of immature brain. Therefore, an unbalance of GABAergic and glutamatergic transmission can explain, at least in part, the high incidence of epilepsy in these patients. Other paediatric diseases that are characterized by the presence of refractory seizures, as Dravet and Angelman syndromes, could share with TSC and FCD a common feature of loss of GABAergic function. Our main goal, using electrophysiological and molecular approaches, is to study the GABAA and AMPA evoked currents in aforementioned human paediatric diseases, in order to suggest new therapies, that could consider not only the primary causes of the diseases, but also a broader scenario of an aberrant neurotransmission underlying epilepsy and the consequent cognitive impairment. We will use human cortical tissues from autopsies of refractory epileptic syndromes (Dravet, TSC, FCD, Rett, Angelman) and age-matched controls to study whether: (1) GABAA transmission is less inhibitory; (2) both AMPA and GABAA subunits expression maintain an immature profile; (3) new drugs could act on the altered neuro- transmission with low side-effects. We intend to demonstrate that a dysfunction of the GABAergic system can contribute to a general reduction of inhibitory efficacy in epileptic syndromes of childhood suggesting that GABAA receptors could be a target for new add-on therapies. Of note, an altered neurotransmission, as feature of brain immaturity, could also contribute to the observed cognitive impairment and intellectual disabilities.
Epilepsy affects more than 1-2% of the worldwide population (WHO) being one of the most common neurological disease. Although, understanding of childhood epilepsy has advanced, an effective treatment intervention is still lacking and about 30-40% of the patients are refractory to the common antiepileptic drugs (AEDs). In addition, drug-resistant epilepsy is associated with high costs that affect individuals and society. Indeed, the pathologies related to a delay or absence of the normal development of nervous system, independently by the different causative mutations, have a common pattern of brain immaturity, intellectual disabilities, cognitive impairment and, in many cases, epilepsy. Therefore, our main objective is to find common hallmarks of brain immaturity in epileptic developmental syndromes with different mutated genes that can induce or worsen the generation and recurrence of seizures in children. Our rationale is that the brain immaturity can be displayed also as an unbalance of inhibitory/excitatory neurotransmission in line with previous studies. We intend to demonstrate, using human tissues surgically resected from pediatric patients, that GABAergic transmission is aberrant and extremely immature especially in comparison with AMPA mediated transmission. The microtransplantation approach is very powerful and innovative, because we can study functional receptors from human samples with limited availability to obtain brain slices or even isolated neurons. We think that our project has a high scientific impact because, acting on the function of neurotransmitters, we can improve the therapeutic management of the generation and recurrence of seizures. If our hypothesis will be validated, we could propose 'common' drugs that act on neurotransmitter systems in the poly-therapy for 'specific' and rare epileptic diseases.
The potential of our research is based on the two different points:
1. Our study is one of the few on pediatric patients and it will be performed using rare samples of human tissues to overcome the limitation of the use of animal models
2. For the originality of the approaches and therapeutic implications, our study is appealing not only for the pharmacological research, but also for the families of patients that are very interested to have an immediate and concrete application from the research that, aiming at an improvement of epileptic pathology, can ameliorate the quality of the children life.
Relevant literature (in alphabetical order).
Aronica et al., 2007. Neuroscience; 151(1):272-92.
Ben-Ari et al., 1997. Trends Neurosc; 20(11):523-9.
Ben-Ari et al., 2012. Neuroscientist.18(5):467-86.
Blumcke et al., 2011. Epilepsia; 52(1):158-74.
Cepeda et al., 2014. Neurobiol Dis;62:208-17
Conti et al., 2014. Clin Genet; 88(3):241-7
Crino, et al., 2011. Trends Mol Med, 17(12), 734-742.
Eusebi et al., 2009. Progr in Neurobiol; 88: 32-40.
Faulkner and Singh. 2013. Pharmacotherapy. 33(3):330-43.
Jansen et al., 2015. Brain; 138(Pt 6):1613-28.
Kang and Macdonald, 2016 JAMA Neurol; 1;73(8):1009-16.
Kaplan et al., 2017 Proc Natl Acad Sci U S A; 17;114(42):11229-11234.
Krsek et al., 2013. Epilepsia; 54(11):1913-21.
Kwan et al., 2010. Epilepsia;51(6):1069-77.
Lalande and Calciano, 2007. Cell Mol Life Sci. 64(7-8):947 60.
Liu et al., 2014.. Acta Neuropathol Commun 2, 71-5960-2-71.
Morano et al., 2016. Epilepsia Open; 19;1(3-4):145-151.
Palma et al., 2003. Proc. Natl. Acad. Sci.; 4, 2896-2900
Palma et al., 2006.Proc Natl Acad Sci U S A; 1;103(31):11814.
Roseti et al., 2013.Epilepsia; 54(10):1834-44.
Ruffolo et al., 2016 Neurobiol Dis; 95:93-101
Schick et al., 2007. Brain pathology; 2007;17(2):165-73.
Talos et al., 2012. Ann Neurol; 71(4):539-51.
Tang et al., 2016. Proc Natl Acad Sci U S A;113(3):751-6.
Tang and Fang 201. N Engl J Med.17;377(7):699