GABARAPs dysfunction by autophagy deficiency in adolescent brain impairs GABA _A receptor trafficking and social behavior

Abstract

Dysfunctional mTOR signaling is associated with the pathogenesis of neurodevelopmental and neuropsychiatric disorders. However, it is unclear what molecular mechanisms and pathogenic mediators are involved and whether mTOR-regulated autophagy continues to be crucial beyond neurodevelopment. Here, we selectively deleted Atg7 in forebrain GABAergic interneurons in adolescent mice and unexpectedly found that these mice showed a set of behavioral deficits similar to Atg7 deletion in forebrain excitatory neurons. By unbiased quantitative proteomic analysis, we identified γ-aminobutyric acid receptor–associated protein-like 2 (GABARAPL2) to differentially form high–molecular weight species in autophagy-deficient brains. Further functional analyses revealed a novel pathogenic mechanism involving the p62-dependent sequestration of GABARAP family proteins, leading to the reduction of surface GABAA receptor levels. Our work demonstrates a novel physiological role for autophagy in regulating GABA signaling beyond postnatal neurodevelopment, providing a potential mechanism for the reduced inhibitory inputs observed in neurodevelopmental and neuropsychiatric disorders with mTOR hyperactivation.

mTOR-Related Cell-Clearing Systems in Epileptic Seizures, an Update

“…The present data indicate a novel physiological role for autophagy in regulating GABAergic signaling, providing a potential mechanism for the reduced inhibitory inputs observed in neurodevelopmental and neurological disorders such as epilepsy and autism [26]. These findings have bridged the gap between mTOR, autophagy, and GABAergic signaling, which started to emerge in 2009 when the role of autophagy in GABA A receptor trafficking was first demonstrated [51].…”

“…This occurs, for instance, through degradation and turnover of both pre-and post-synaptic substrates, including synaptic vesicles, scaffold proteins, and neurotransmitter receptors [23][24][25]. In keeping with this, failure of mTOR-dependent autophagy was recently shown to promote aberrant synaptic clustering of GABA A receptors and subsequent imbalance of excitation-inhibition in the brain, which might be key for epileptogenesis [26]. Alterations in mTOR-dependent autophagy are also implicated in abnormal dopamine system activity, which is implicated in epileptogenesis as well [27].…”

“…In a similar fashion, autophagy suppression due to TSC2-related mTOR hyperactivation disrupts the trafficking of GABA A receptors via the sequestration of γ-aminobutyric acid receptor-associated proteins (GABARAPs) by p62-positive aggregates [26]. Such an effect is reproduced by autophagy deficiency following either ATG7 or ULK2 deletion in forebrain inhibitory or excitatory neurons [26,49].…”

“…In a similar fashion, autophagy suppression due to TSC2-related mTOR hyperactivation disrupts the trafficking of GABA A receptors via the sequestration of γ-aminobutyric acid receptor-associated proteins (GABARAPs) by p62-positive aggregates [26]. Such an effect is reproduced by autophagy deficiency following either ATG7 or ULK2 deletion in forebrain inhibitory or excitatory neurons [26,49]. In fact, beyond LC3, proteins belonging to the GABARAP family have been shown to be involved in the trafficking of GABA A receptors to the neuronal plasma membrane, and they also have numerous binding partners that are involved in synapse formation, maintenance, and plasticity [23,50].…”

Emerging Role of the Autophagy/Lysosomal Degradative Pathway in Neurodevelopmental Disorders With Epilepsy

“…As recently reviewed, dysfunctional autophagy at both pre-and post-synaptic sites leads to aging and neurodegeneration (Nikoletopoulou et al, 2015;Vijayan and Verstreken, 2017;Azarnia Tehran et al, 2018;Liang and Sigrist, 2018). Degradation of postsynaptic neurotransmitter receptors involves trafficking in autophagosomal structures (Rowland, 2006;Shehata et al, 2012Shehata et al, , 2018Hui et al, 2019). At dopaminergic presynaptic sites, autophagy shapes synapse ultrastructure and modulates neurotransmitter release, while at glutamatergic synapses mTOR-regulated autophagy promotes spine pruning during development (Hernandez et al, 2012;Tang et al, 2014).…”