LRRC57 modulates neurotrophic growth factor signaling in synaptic function and behavior

Abstract Our understanding of the biology of neuropsychiatric disease is still in the early stages. Genome-wide association studies have identified multiple genomic loci associated with such diseases, but the biology of many of those targets is still unknown. In this proposal, we focus on the LRRC57 gene, which was identified among the top

targets for bipolar disorder, a devastating psychiatric condition that affects millions of people around the world and is characterized by extreme mood swings, ranging from mania to depressive episodes, each of which can last for several days. The Lrrc57 gene encodes a 27-kDa horseshoe-shaped protein that belongs to the Leucine-

Rich Repeat domain–Containing proteins and is evolutionarily conserved. LRRC57 is expressed in neurons, and its germline deletion is lethal in flies and worms. Despite its importance, no studies on the biology of LRRC57 have been reported in the literature. Our preliminary data show that germline Lrrc57 deletion is also lethal in

mice. Furthermore, we determined that the LRRC57 protein mediates the function of neurotrophic growth factors, which are important for neural development, synaptic plasticity, and cognition. In preparation of this proposal, we have produced a specific monoclonal anti-LRRC57 antibody and genetically engineered mice with global Lrrc57

deletion, mice with the conditional deletion of Lrrc57 in neurons only, and mice with the conditional overexpression of Lrrc57 in neurons at different developmental stages. Using these tools, we propose to elucidate the biochemical functions of LRRC57 by identifying its interacting protein partners, determining the

functional importance of those interactions, and establishing the molecular profile of the mouse brain upon Lrrc57 deletion or overexpression (Aim 1). We also propose to investigate the role of LRRC57 in neural excitability, synaptic transmission, and long-term synaptic plasticity, with a focus on neurotrophin-dependent forms of

synaptic plasticity in the hippocampus (Aim 2). In this Aim, we will also test cognitive function and bipolar disorder–related behaviors in mice with conditionally deleted or overexpressed Lrrc57. This work will establish the foundation for gaining an understanding of the biology of the previously unrecognized, evolutionarily

conserved Lrrc57 gene and potentially reveal its involvement in bipolar disorder.