Loss of mTOR-Dependent Macroautophagy Causes Autistic-like Synaptic Pruning Deficits

Abstract

Summary Developmental alterations of excitatory synapses are implicated in autism spectrum disorders (ASDs). Here, we report increased dendritic spine density with reduced developmental spine pruning in layer V pyramidal neurons in postmortem ASD temporal lobe. These spine deficits correlate with hyperactivated mTOR and impaired autophagy. In Tsc2+/- ASD mice where mTOR is constitutively overactive, we observed postnatal spine pruning defects, blockade of autophagy, and ASD-like social behaviors. The mTOR inhibitor rapamycin corrected ASD-like behaviors and spine pruning defects in Tsc2+/ mice, but not in Atg7CKO neuronal autophagy deficient mice or Tsc2+/-:Atg7CKO double mutants. Neuronal autophagy furthermore enabled spine elimination with no effects on spine formation. Our findings suggest that mTOR regulated autophagy is required for developmental spine pruning, and activation of neuronal autophagy corrects synaptic pathology and social behavior deficits in ASD models with hyperactivated mTOR.

Collybistin binds and inhibits mTORC1 signaling: a potential novel mechanism contributing to intellectual disability and autism

“…31 In addition, overactivated mTORC1 signaling has also been linked to the pathophysiology of non-syndromic ASD. 10,11,32,33 This hyperactivation of the mTORC1 pathway has been shown to stimulate excessive protein synthesis in neuronal cells, leading to disturbances in neuronal differentiation and morphology, synaptic connectivity, and plasticity. Loss-of-function variants in CB, which are known to reduce GABAergic transmission and alter synaptic plasticity, have been associated with overlapping phenotypes, that is, intellectual disability, epilepsy, anxiety, 15,[22][23][24][25] and now autism, present in the patient here described.…”

“…5 Therefore, dysfunctional mTORC1 signaling and dysregulated protein synthesis in neuronal cells have been associated with several neurodevelopmental disorders with intellectual disability and autism. [6][7][8][9][10][11] mTORC1 signaling modulates assembly of the translation initiation machinery by interacting with the eukaryotic initiation factor eIF3, a scaffold complex that brings all components of the translation initiation process into close proximity, and by coordinating the phosphorylation and activity of key translational regulators S6K1 and 4EBP1. 12 We have recently identified two novel binding partners for eIF3, the neural Rho-GEF collybistin (CB) and the synaptic scaffold protein gephyrin, 13 which are known to be required for GABA A receptors clustering and inhibitory synapse formation.…”

Autophagy in synaptic development, function, and pathology

“…The time course of spine development in primary cultured hippocampal neurons is similar to that of dendritic spines in mouse brain [30,31] . In cultured neurons, the number of spines increases during 6-10 days in vitro (DIV), peaks at 14-21 DIV, and decreases after 21-28 DIV [32] . Tang increases the spine density at 19-20 DIV [32] .…”

“…In cultured neurons, the number of spines increases during 6-10 days in vitro (DIV), peaks at 14-21 DIV, and decreases after 21-28 DIV [32] . Tang increases the spine density at 19-20 DIV [32] . Interestingly, unlike control cells in which the rates of synapse formation and elimination are approximately equivalent, hippocampal neurons deficient in atg7 exhibit normal spine formation but greatly inhibited elimination, indicating that autophagy enables synaptic elimination in cultured hippocampal neurons during the "mature" developmental stage [32,33] .…”

Information and knowing when to forget it

“…Indeed, there is an increasing amount of evidence which demonstrates the importance forgetting in human learning. For example, recent work in neurology suggests that the development of cognitive disorders lying on the autism spectrum [11] is associated with the malfunctioning of the synaptic pruning process [12], [13]. This leads to over-connectedness in certain areas of the brain and explains a range of impairments in social interaction and communication, such as compulsiveness and repetitive motor behaviour [14].…”