Contributions of the mTOR pathway to striatal alterations in environmental and genetic models of autism
Autism Spectrum Disorders (ASDs) are amongst the most prevalent neurodevelopmental disorders, and are characterized by repetitive behaviours, social impairment and cognitive inflexibility. Neuropathological studies in both ASDs patients and animal models recurrently reveal morphological and functional alterations in several brain regions, notably the striatum (STR). As the main input nucleus of the basal ganglia, the striatum plays a central role in motor control, cognitive flexibility, social behaviour, and learning. The STR is predominantly composed of Spiny Projection Neurons (SPNs), whose activity is modulated by dopamine (DA).
ASDs are polygenic disorders arising from the interplay between susceptibility genes, epigenetic regulation, and environmental factors. Many genetic and environmental models of ASDs converge on dysregulated mammalian Target Of Rapamycin (mTOR) signalling. mTORC1, a key complex in this pathway, regulates autophagy and protein synthesis. Hyperactivation of mTORC1 leads to impaired autophagic flux and enhanced translation, both of which have been implicated in ASDs pathophysiology; yet their relative contributions remain poorly understood. This thesis investigates the impact of dysregulated mTORC1-signalling over striatal development and function in environmental and genetic models of ASDs.
In Paper I we characterized the roles of neuronal autophagy in the development of the STR during the postnatal period. Along this time window, mTORC1 activity steadily increases, which results in a gradual reduction in autophagic activity in SPNs. Furthermore, we provide evidence that in utero exposure to valproic acid leads to mTORC1 hyperactivity at late developmental stages, which inhibits autophagic flux. This mTORC1 overactivation results in impaired sociability and decreased glutamatergic synaptic transmission.
In Paper II we investigated the consequences of translational dysregulation over striatal dopaminergic modulation. Increased translation leads to altered dopaminergic transmission, due to impaired nicotinic receptors on DA terminals. This defective cholinergic modulation of DA terminals, in turn, underlies cognitive inflexibility.
Altogether, the work presented in this thesis sheds new light onto the consequences of mTOR signalling dysregulation over striatal function in environmental and genetic models of ASDs.
List of scientific papers
I. mTOR supresses macroautophagy during striatal postnatal development and is hyperactive in mouse models of autism spectrum disorders
https://doi.org/10.3389/fncel.2020.00070
II. Dysregulated acetylcholine-mediated dopamine neurotransmission in the eIF4E Tg mouse model of autism spectrum disorders
https://doi.org/10.1016/j.celrep.2024.114997
History
Defence date
2025-06-13Department
- Department of Neuroscience
Publisher/Institution
Karolinska InstitutetMain supervisor
Emanuela SantiniCo-supervisors
Anders Borgkvist; Gilad SilberbergPublication year
2025Thesis type
- Doctoral thesis
ISBN
978-91-8017-609-5Number of pages
100Number of supporting papers
2Language
- eng