- Awarded: 2020
- Award Type: Pilot
- Award #: 736666
Tuberous sclerosis complex (TSC) is a genetic condition caused by inactivating mutations in TSC1 or TSC2 genes, with variable penetrance and severity. The brain is among the most affected organs in individuals with TSC and the neurological manifestations are often the most devastating, particularly in children carrying mutations in TSC2. The proteins encoded by TSC1 and TSC2 cooperate to inhibit mTORC1, a protein complex critical for protein synthesis.
Consistently, genes encoding proteins involved in regulating translation at the synapse are frequently mutated in autism spectrum disorder (ASD), which has led to the suggestion that altered protein synthesis is a core pathophysiological mechanism of intellectual disability and autism. The identification of molecules regulated by local translation, which are crucial for the development of specific neural circuits affected in ASD, remains a major challenge in the field.
Preliminary findings from Oscar Marín and Beatriz Rico’s labs indicate that synaptic Tsc2 is specifically regulated by the tyrosine kinase receptor ErbB4 in parvalbumin-expressing (PV+) cortical interneurons during the period of synaptogenesis in the mouse. These observations suggest that Tsc2 is normally inhibited by ErbB4 signaling during the formation of excitatory synapses onto PV+ interneurons, which implies that the regulation of local translation is important in this process.
Based on these findings, Marín and Rico hypothesize that changes in the formation of excitatory synapses onto PV+ interneurons are critical in the pathophysiology of TSC and perhaps other forms of ASD. To test this hypothesis, they aim to: (i) genetically link Tsc2 and local translation in the formation of excitatory synapses onto cortical PV+ interneurons and (ii) identify molecular targets mediating the function of Tsc2-mTOR signaling at the synapse in cortical interneurons. Interneuron-specific Tsc2 and ErbB4 conditional mutant mouse lines will be used for these studies.
This project will shed light into the molecular mechanisms through which local translation regulates the development of a specific pool of synapses — the excitatory inputs received by cortical PV+ interneurons — which are affected in several animal models of ASD. Findings from this work would therefore identify biological convergence across specific neural circuits and signaling pathways in autism.
- Interneuron subtype-specific malfunction in autism spectrum disorders
- Assembly of cortical microcircuit motifs in a mouse model of Arid1b haploinsufficiency
- Investigating the mechanisms of FMRP dysregulation due to the loss of TSC2
- Parvalbumin down-regulation as a common pathophysiological mechanism in autism spectrum disorders
- Role of GABA interneurons in a genetic model of autism
- Regulation of cortical circuits by TSC1 in GABAergic interneurons