ErbB4 Can Promote Inhibitory Synapse Formation by Cell Adhesion, Independent of Its Kinase Activity

Luo et al.

Bin Luo¹, Ziyang Liu¹, Wenbin Chen¹, Peng Chen¹, Erkang Fei¹, and Lin Mei^{2, 3}

1. Institute of Life Science, Nanchang University, Nanchang, China
2. Department of Neurosciences, School of Medicine, Case Western Reserve University, Cleveland, OH 
3. Louis Stokes Cleveland Veterans Affairs Medical Center, Cleveland, OH

ErbB4 plays a critical role in neurodevelopment and has been suggested as susceptibility gene of schizophrenia. Although it is well-known as a tyrosine kinase, ErbB4’s function independent of its kinase activity remains unknown. To address this question, we first transfected a kinase-deficient ErbB4 gene into HEK293T cells and found induction of postsynaptic clustering in co-cultured neurons. To further confirm whether kinase activity is important for the functioning of ErbB4, we generated ErbB4-K751M mice, which loss their kinase activity from germ cells. Surprisingly, we found that ErbB4-K751M mice showed normal interneuron migration, inhibitory synapse formation and neurotransmission. Behavioral tests including open field test, contextual fear-conditioning and pre-pulse inhibition showed no deficits either. Notably, co-IP suggests an interaction between ErbB4 and SLIT And NTRK Like Family Member 3 (Slitrk3) which locates at the inhibitory postsynaptic site and is critical for synapse formation. After blocking this interaction, the synaptic transmission decreased in a non-cell autonomous manner. These observations indicate that in contrast to its known kinase activity, ErbB4’s more important role, therefore, might be as a cell adhesion molecule interacting with Slitrk3 at the synapse. Together, ErbB4 might function as a cell adhesion molecule that is important in both neurodevelopment and neurotransmission.