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 3 β) 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 (Map6(+/-)) 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.
Keywords: ADNP, activity-dependent neuroprotector homeobox (human); Adnp, activity-dependent neuroprotective protein (mouse); Adnp2 (mouse), ADNP2 (human), ADNP homeobox 2; Becn1 (mouse), BECN1 (human), Beclin 1, autophagy-related; CLZ, clozapine; HUGO gene nomenclature committee database); Hprt/Hprt1, hypoxanthine phosphoribosyl transferase; MGI database); Map1lc3b (mouse), MAP1LC3B (human), microtubule-associated protein 1 light chain 3 β; Map6 (mouse), MAP6 (human), microtubule-associated protein 6; NAP (davunetide); object recognition; activity-dependent neuroprotective protein (ADNP; activity-dependent neuroprotector homeobox (ADNP; hyperactivity; immunohistochemistry; microtubule-associated protein 6 (MAP6)/stable tubule only polypeptide (STOP) deficiency; real-time PCR.