New horizons in schizophrenia treatment: Autophagy protection is coupled with behavioral improvements in a mouse model of schizophrenia

Avia Merenlender-Wagner, Zeev Shemer, Olga Touloumi, Roza Lagoudaki, Eliezer Giladi, Annie Andrieux, Nikolaos C. Grigoriadis, Illana Gozes*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review


Autophagy plays a key role in the pathophysiology of schizophrenia as manifested by a 40% decrease in BECN1/ Beclin 1 mRNA in postmortem hippocampal tissues relative to controls. This decrease was coupled with the deregulation of the essential ADNP (activity-dependent neuroprotector homeobox), a binding partner of MAP1LC3B/ LC3B (microtubule-associated protein 1 light chain 3β) another major constituent of autophagy. The drug candidate NAP (davunetide), a peptide fragment from ADNP, enhanced the ADNP-LC3B interaction. Parallel genetic studies have linked allelic variation in the gene encoding MAP6/STOP (microtubule-associated protein 6) to schizophrenia, along with altered MAP6/STOP protein expression in the schizophrenic brain and schizophrenic-like behaviors in Map6-deficient mice. In this study, for the first time, we reveal significant decreases in hippocampal Becn1 mRNA and reversal by NAP but not by the antipsychotic clozapine (CLZ) in Map6-deficient (Map6C+/-) mice. Normalization of Becn1 expression by NAP was coupled with behavioral protection against hyperlocomotion and cognitive deficits measured in the object recognition test. CLZ reduced hyperlocomotion below control levels and did not significantly affect object recognition. The combination of CLZ and NAP resulted in normalized outcome behaviors. Phase II clinical studies have shown NAP-dependent augmentation of functional activities of daily living coupled with brain protection. The current studies provide a new mechanistic pathway and a novel avenue for drug development.

Original languageEnglish
Pages (from-to)2324-2332
Number of pages9
Issue number12
StatePublished - 1 Dec 2014


FundersFunder number
Adams family
Allon Therapeutics Inc.
Canadian Friends of Tel Aviv University
AAMN Foundation
Tel Aviv University
Adams Super Center for Brain Studies,Tel Aviv University


    • Activity-dependent neuroprotective protein (ADNP, MGI database)
    • Activity-dependent neuroprotector homeobox (ADNP, HUGO gene nomenclature committee database)
    • Hyperactivity
    • Immunohistochemistry
    • Microtubule-associated protein 6 (MAP6)/stable tubule only polypeptide (STOP) deficiency
    • NAP (davunetide)
    • Object recognition
    • Real-time PCR


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