Autophagy has a key role in the pathophysiology of schizophrenia

Mol Psychiatry. 2015 Feb;20(1):126-32. doi: 10.1038/mp.2013.174. Epub 2013 Dec 24.


Autophagy is a process preserving the balance between synthesis, degradation and recycling of cellular components and is therefore essential for neuronal survival and function. Several key proteins govern the autophagy pathway including beclin1 and microtubule associated protein 1 light chain 3 (LC3). Here, we show a brain-specific reduction in beclin1 expression in postmortem hippocampus of schizophrenia patients, not detected in peripheral lymphocytes. This is in contrast with activity-dependent neuroprotective protein (ADNP) and ADNP2, which we have previously found to be deregulated in postmortem hippocampal samples from schizophrenia patients, but that now showed a significantly increased expression in lymphocytes from related patients, similar to increases in the anti-apoptotic, beclin1-interacting, Bcl2. The increase in ADNP was associated with the initial stages of the disease, possibly reflecting a compensatory effect. The increase in ADNP2 might be a consequence of neuroleptic treatment, as seen in rats subjected to clozapine treatment. ADNP haploinsufficiency in mice, which results in age-related neuronal death, cognitive and social dysfunction, exhibited reduced hippocampal beclin1 and increased Bcl2 expression (mimicking schizophrenia and normal human aging). At the protein level, ADNP co-immunoprecipitated with LC3B suggesting a direct association with the autophagy process and paving the path to novel targets for drug design.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Animals
  • Antipsychotic Agents / pharmacology
  • Apoptosis Regulatory Proteins / metabolism
  • Autophagy / ethics*
  • Autophagy / genetics
  • Autophagy / physiology
  • Beclin-1
  • Case-Control Studies
  • Cell Line, Transformed
  • Clozapine / pharmacology
  • Female
  • Hippocampus / metabolism*
  • Hippocampus / pathology*
  • Homeodomain Proteins / genetics
  • Humans
  • Lymphocytes / drug effects
  • Lymphocytes / metabolism
  • Male
  • Mice
  • Mice, Knockout
  • Microtubule-Associated Proteins / genetics
  • Microtubule-Associated Proteins / metabolism
  • Middle Aged
  • Nerve Tissue Proteins / deficiency
  • Nerve Tissue Proteins / genetics
  • Neuroblastoma / pathology
  • Rats
  • Rats, Sprague-Dawley
  • Schizophrenia / pathology*
  • Schizophrenia / physiopathology*
  • Young Adult
  • bcl-Associated Death Protein / genetics
  • bcl-Associated Death Protein / metabolism


  • ADNP protein, human
  • Antipsychotic Agents
  • Apoptosis Regulatory Proteins
  • Beclin-1
  • Becn1 protein, rat
  • Homeodomain Proteins
  • Map1lc3b protein, mouse
  • Microtubule-Associated Proteins
  • Nerve Tissue Proteins
  • bcl-Associated Death Protein
  • Clozapine