SlgA, encoded by the homolog of the human schizophrenia-associated gene PRODH, acts in clock neurons to regulate Drosophila aggression.

Liesbeth Zwarts,Edgar Buhl,Patrick Callaerts,James J L Hodge,Veerle Vulsteke

doi:10.1242/dmm.027151

Liesbeth Zwarts, Edgar Buhl + Show 3 more

Open Access

https://doi.org/10.1242/dmm.027151

Copy DOI

Abstract

ABSTRACTMutations in the proline dehydrogenase gene PRODH are linked to behavioral alterations in schizophrenia and as part of DiGeorge and velo-cardio-facial syndromes, but the role of PRODH in their etiology remains unclear. Here, we establish a Drosophila model to study the role of PRODH in behavioral disorders. We determine the distribution of the Drosophila PRODH homolog slgA in the brain and show that knockdown and overexpression of human PRODH and slgA in the lateral neurons ventral (LNv) lead to altered aggressive behavior. SlgA acts in an isoform-specific manner and is regulated by casein kinase II (CkII). Our data suggest that these effects are, at least partially, due to effects on mitochondrial function. We thus show that precise regulation of proline metabolism is essential to drive normal behavior and we identify Drosophila aggression as a model behavior relevant for the study of the mechanisms that are impaired in neuropsychiatric disorders.

Highlights

Loss of proline dehydrogenase (PRODH) has been linked to various behavioral defects
We found prominent expression in the lateral neurons ventral (LNv), the main pacemaker cells of the Drosophila clock, which express Pigment-dispersing factor (Pdf ), and in cells located in the suboesophageal ganglion (SOG) (Fig. 1A-D)
PRODH has been associated with different psychiatric disorders that are characterized by alterations in social behavior (Jacquet et al, 2002; Li et al, 2004; Liu et al, 2002)

Summary

Introduction

Human PRODH maps to 22q11, a chromosomal region associated with the most frequently observed interstitial deletion in humans and linked to different diseases, including DiGeorge and velo-cardio-facial syndrome (Scambler, 2000). Individuals with these disorders often show cognitive, behavioral or personality problems (Gerdes et al, 1999; Kok and Solman, 1995; Swillen et al, 1999). Multiple studies point towards a direct association of this deletion with psychiatric disorders such as schizophrenia and bipolar disorder PRODH-deficient mice have been shown to have a sensorimotor-gating defect, a defect considered an important endophenotype of schizophrenia (Gogos et al, 1999)

Methods

Results

Conclusion