Microbiota changes associated with ADNP deficiencies: rapid indicators for NAP (CP201) treatment of the ADNP syndrome and beyond

J Neural Transm (Vienna). 2020 Feb;127(2):251-263. doi: 10.1007/s00702-020-02155-5. Epub 2020 Feb 18.

Abstract

Activity-dependent neuroprotective protein (ADNP) and its protein snippet NAP (drug candidate CP201) regulate synapse formation and cognitive as well as behavioral functions, in part, through microtubule interaction. Given potential interactions between the microbiome and brain function, we now investigated the potential effects of the ADNP-deficient genotype, mimicking the ADNP syndrome on microbiota composition in the Adnp+/- mouse model. We have discovered a surprising robust sexually dichotomized Adnp genotype effect and correction by NAP (CP201) as follows. Most of the commensal bacterial microbiota tested were affected by the Adnp genotype and corrected by NAP treatment in a male sex-dependent manner. The following list includes all the bacterial groups tested-labeled in bold are male Adnp-genotype increased and corrected (decreased) by NAP. (1) Eubacteriaceae (EubV3), (2) Enterobacteriaceae (Entero), (3) Enterococcus genus (gEncocc), (4) Lactobacillus group (Lacto), (5) Bifidobacterium genus (BIF), (6) Bacteroides/Prevotella species (Bac), (7) Clostridium coccoides group (Coer), (8) Clostridium leptum group (Cluster IV, sgClep), and (9) Mouse intestinal Bacteroides (MIB). No similarities were found between males and females regarding sex- and genotype-dependent microbiota distributions. Furthermore, a female Adnp+/- genotype associated decrease (contrasting male increase) was observed in the Lactobacillus group (Lacto). Significant correlations were discovered between specific bacterial group loads and open-field behavior as well as social recognition behaviors. In summary, we discovered ADNP deficiency associated changes in commensal gut microbiota compositions, a sex-dependent biomarker for the ADNP syndrome and beyond. Strikingly, we discovered rapidly detected NAP (CP201) treatment-dependent biomarkers within the gut microbiota.

Keywords: Activity-dependent neuroprotective protein (ADNP); Autism; Behavior; Microbiota; NAP (CP201).

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Autism Spectrum Disorder / drug therapy*
  • Autism Spectrum Disorder / microbiology
  • Autism Spectrum Disorder / physiopathology
  • Behavior, Animal* / drug effects
  • Disease Models, Animal
  • Female
  • Gastrointestinal Microbiome* / drug effects
  • Genotype
  • Homeodomain Proteins / genetics
  • Male
  • Mice
  • Mice, Transgenic
  • Naphthoquinones / administration & dosage
  • Naphthoquinones / pharmacokinetics
  • Naphthoquinones / pharmacology*
  • Nerve Tissue Proteins / deficiency*
  • Nerve Tissue Proteins / genetics
  • Social Behavior
  • Social Cognition
  • Syndrome

Substances

  • 2-(3,5-di-tert-butyl-4-hydroxyl)-3-chloro-1,4-naphthoquinone
  • Adnp protein, mouse
  • Homeodomain Proteins
  • Naphthoquinones
  • Nerve Tissue Proteins