sAPPalpha inhibits neurite outgrowth in primary mouse neurons via GABA B Receptor subunit 1a

Abstract

Neurite outgrowth is essential for neural circuit formation and is tightly regulated by secreted factors and their receptors. The secreted extracellular domain of the amyloid precursor protein (sAPP) has been shown to modulate neurite outgrowth. Recently, the gamma amino butyric acid receptor type-B subunit 1a (GABABR1a) was identified as an sAPP binding partner that mediates its effects on synaptic transmission. Here, we investigated whether this interaction also regulates neurite outgrowth. In primary hippocampal neurons, the GABABR agonist baclofen reduced axon length; whereas, its antagonist CGP54626 increased axon length in primary hippocampal neurons. Moreover, GABABR1a knockout increased axon length and abolished the effect of baclofen. Application of sAPP reduced axon length, an effect that required the presence of both GABABR1a and the extension domain of sAPP, which mediates its binding to GABABR1a. Similarly, the APP 17mer peptide, which is sufficient to bind GABABR1a and mimic the effects of sAPP on synaptic transmission, reduced axon outgrowth in wildtype but not in GABABR1a-deficient neurons. Together, these findings indicate that the 1a isoform contributes to GABABR-dependent suppression of neurite outgrowth and mediates the inhibitory effect of sAPP on neurite outgrowth. Statement of SignificanceAmyloid precursor protein (APP) plays a central role in Alzheimers disease, yet its normal functions are not fully understood. In this study, we uncover a previously unrecognized role of the GABA B Receptor in mediating the inhibitory effects of sAPP on neurite outgrowth. These findings provide mechanistic insight into how disruptions in APP signaling could influence both normal brain development and pathological processes in neurodevelopmental disorders and Alzheimers disease.