ArticleHuman molecular genetics2018
Ulk2 controls cortical excitatory-inhibitory balance via autophagic regulation of p62 and GABAA receptor trafficking in pyramidal neurons.
Article in Human molecular genetics, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 31 papers.
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Who cites it
31 citing papers in PubMed, 52 citations in OpenAlex.
- The intrinsic excitability of and autophagy protein expression levels in dentate gyrus ensembles regulate fear generalization.Neural regeneration research · 2026Article
- Autophagy in Schizophrenia: A Continuum From Developmental Vulnerability to Progressive Neuronal Stress? A Scoping Review.Schizophrenia bulletin · 2026Article
- Selective magnetic stimulation downregulates the GABAMolecular psychiatry · 2026Article
- Review
- Exploring Dapagliflozin's Influence on Autophagic Flux in Mania-like Behaviour: Insights from the LKB1/AMPK/LC3 Pathway in a Mouse Model.Journal of neuroimmune pharmacology : the official journal of the Society on NeuroImmune Pharmacology · 2025Article
- Neuronal autophagy controls excitability via ryanodine receptor-mediated regulation of calcium-activated potassium channel function.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- Aberrant aging-associated p62 autophagic cascade in biopsied olfactory neuronal cells from patients with psychosis.Schizophrenia (Heidelberg, Germany) · 2025Article
- Perturbed cell fate decision by schizophrenia-associated AS3MTScience advances · 2025Article
- Article
- Impaired neuronal macroautophagy in the prelimbic cortex contributes to comorbid anxiety-like behaviors in rats with chronic neuropathic pain.Autophagy · 2024Article
- Review
- Autophagy markers, cognitive deficits and depressive symptoms in Parkinson's disease.Journal of neural transmission (Vienna, Austria : 1996) · 2024Article
- Zinc Oxide Nanoparticles Exacerbate Epileptic Seizures by Modulating the TLR4-Autophagy Axis.International journal of nanomedicine · 2024Article
- Analysis revealed the molecular mechanism of oxidative stress-autophagy-induced liver injury caused by high alkalinity: integrated whole hepatic transcriptome and metabolome.Frontiers in immunology · 2024Article
- Macroautophagy in CNS health and disease.Nature reviews. Neuroscience · 2022Review
- Molecular origin of somatostatin-positive neuron vulnerability.Molecular psychiatry · 2022Article
- Regulation of sensorimotor gating via Disc1/Huntingtin-mediated Bdnf transport in the cortico-striatal circuit.Molecular psychiatry · 2022Article
- A Perspective on the Potential Involvement of Impaired Proteostasis in Neuropsychiatric Disorders.Biological psychiatry · 2022Review
- Olfactory neuronal cells as a promising tool to realize the "druggable genome" approach for drug discovery in neuropsychiatric disorders.Frontiers in neuroscience · 2022Article
- BDNF controls GABANeuropsychopharmacology : official publication of the American College of Neuropsychopharmacology · 2022Article
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Authors and funding
19 authors at 5 institutions in 3 countries.
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Abstract
Autophagy plays an essential role in intracellular degradation and maintenance of cellular homeostasis in all cells, including neurons. Although a recent study reported a copy number variation of Ulk2, a gene essential for initiating autophagy, associated with a case of schizophrenia (SZ), it remains to be studied whether Ulk2 dysfunction could underlie the pathophysiology of the disease. Here we show that Ulk2 heterozygous (Ulk2+/-) mice have upregulated expression of sequestosome-1/p62, an autophagy-associated stress response protein, predominantly in pyramidal neurons of the prefrontal cortex (PFC), and exhibit behavioral deficits associated with the PFC functions, including attenuated sensorimotor gating and impaired cognition. Ulk2+/- neurons showed imbalanced excitatory-inhibitory neurotransmission, due in part to selective down-modulation of gamma-aminobutyric acid (GABA)A receptor surface expression in pyramidal neurons. Genetically reducing p62 gene dosage or suppressing p62 protein levels with an autophagy-inducing agent restored the GABAA receptor surface expression and rescued the behavioral deficits in Ulk2+/- mice. Moreover, expressing a short peptide that specifically interferes with the interaction of p62 and GABAA receptor-associated protein, a protein that regulates endocytic trafficking of GABAA receptors, also restored the GABAA receptor surface expression and rescued the behavioral deficits in Ulk2+/- mice. Thus, the current study reveals a novel mechanism linking deregulated autophagy to functional disturbances of the nervous system relevant to SZ, through regulation of GABAA receptor surface presentation in pyramidal neurons.
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