Molecular Mechanisms of Brain Function in mTOR-Deficient Intellectual Disability Syndromes


Mammalian target of rapamycin (mTOR) deficiency has been demonstrated to be an important pathobiochemical feature in several genetic syndromes that are characterized by cognitive impairment. Among these are Rett syndrome (RTT) caused by mutations in MECP2, CDKL5 deficiency (CD, previously known as atypical RTT) and Opitz/BBB/G syndrome (OS). We were the first groups who have identified mutations in CDKL5 and MID1 as the underlying causes for CD and OS. Furthermore, we have significantly contributed to the identification of basic mechanisms of CDKL5, MeCP2 and MID1 protein functions and to the understanding of the molecular pathogenesis underlying these syndromes. In the current proposal we will undertake a multidisciplinary and international co-operative approach to further link these syndromes with mTOR activity and brain function. We will use in vitro and in vivo model systems and will combine biochemical, cellular, electrophysiological and mouse behavior approaches in order to answer the fundamental question of how mTOR dependent protein synthesis translates into synaptic plasticity and learning and memory. Within the project we hope to gain insight into the (i) role of mTOR signaling in brain function and (ii) the influence of its deficiency in the pathogenesis of intellectual disability (ID). These data will be fundamental for the differential diagnosis of ID and in the future may also open new avenues for the development of novel therapeutic strategies for patients with intellectual disability syndromes and other related disorders


Pharmacology, Electrophisiological approaches, Behavioural methodologies, (epi)genetic approaches, "omics" approaches, aetiology, Intellectual disability, Rett syndrome, CDKL5 disorder, Opitz/BBB/G syndrome, mTOR deficiency, mouse models

Call topic

Mental Disorders

Proposed runtime

2014 - 2017

Project team

Vera Kalscheuer (Coordinator)
Germany (BMBF)
Vania Broccoli
Italy (MOH)
Susann Schweiger
Germany (BMBF)
Rainer Schneider
Austria (FWF)