Editors' ChoiceNeuroscience

Autophagy Goes Social

Sci. Signal.  09 Sep 2014:
Vol. 7, Issue 342, pp. ec242
DOI: 10.1126/scisignal.2005876

Patients with autism spectrum disorders (ASDs) have deficits in communication and other social behaviors. ASDs are heritable, but the genetic etiologies are diverse. Patients with the multisystem disorder tuberous sclerosis complex (TSC), which results from autosomal dominant mutations in TSC1 or TSC2, present with ASD. TSC1 and TSC2 form a heterodimeric complex that inhibits the kinase mTOR (mechanistic target of rapamycin). In the multiprotein complex mTORC1, defined by the presence of Raptor, mTOR promotes protein synthesis and inhibits autophagy, a cellular process used to recycle proteins and organelles. Mice deficient for Tsc1 or Tsc2 have active mTORC1 and ASD-like symptoms. Tang et al. found that regions of the cerebral cortex of ASD patients had decreased pruning of neuronal dendritic spines, which is a part of normal brain maturation; increased mTORC1 activity; and decreased autophagy. Mice with a heterozygous inactivating mutation in Tsc2 (Tsc2+/– mice) or mice with conditional knockout of Tsc1 in cortical neurons (Tsc1CKO mice) had decreased pruning of dendritic spines in the cortex. Tsc2+/– mice had defects in autophagy in the cortex, and mice with cortical neuron–specific knockout of the autophagy-related gene Atg7 (Atg7CKO mice) had decreased pruning of dendritic spines and ASD-like behavioral symptoms. Knockdown of Atg7 in cultured primary hippocampal neurons also reduced spine pruning. Injection with the mTORC1 inhibitor rapamycin reversed the pruning and behavioral deficits in Tsc2+/– mice, but not in Atg7CKO mice, and to a lesser degree in Tsc2+/–;Atg7CKO mice. Thus, excessive or dysregulated mTORC1 activity may contribute to ASD symptoms by preventing synaptic pruning through both autophagy and other mTORC1-dependent mechanisms (see Bowling and Klann).

G. Tang, K. Gudsnuk, S.-H. Kuo, M. L. Cotrina, G. Rosoklija, A. Sosunov, M. S. Sonders, E. Kanter, C. Castagna, A. Yamamoto, Z. Yue, O. Arancio, B. S. Peterson, F. Champagne, A. J. Dwork, J. Goldman, D. Sulzer, Loss of mTOR-dependent macroautophagy causes autistic-like synaptic pruning deficits. Neuron 83, 1131–1143 (2014). [PubMed]

H. Bowling, E. Klann, Shaping dendritic spines in autism spectrum disorder: mTORC1-dependent macroautophagy. Neuron 83, 994–996 (2014). [PubMed]