Axonal Type III Nrg1 Controls Glutamate Synapse Formation and GluA2 Trafficking in Hippocampal-Accumbens Connections

Abstract

Altered neuregulin 1 (Nrg1)/ErbB signaling and glutamatergic hypofunction have been implicated in the pathophysiology of schizophrenia. Here, we employed gene chimeric ventral Hippocampus (vHipp) – accumbens (nAcc) co-culture from mouse, electrophysiology, immunocytochemistry, FM1-43 vesicle fusion and electron microscopy techniques to examine the pre- and post-synaptic mechanisms of genetic deficits in Nrg1/ErbB signaling induced glutamatergic dysfunctions. Reduced presynaptic type III Nrg1 expression along vHipp axons decreases the number of glutamate synapses and impairs GluA2 trafficking in the postsynaptic nAcc neurons, resulting in decreased frequency and amplitude of miniature excitatory postsynaptic currents (mEPSCs). Reduced expression of axonal type III Nrg1 along vHipp projections also decreases functional synaptic vesicle clustering and vesicular trafficking to presynaptic vHipp axonal terminals. These findings suggest that Nrg1/ErbB signaling modulate glutamatergic transmission via both pre- and post-synaptic mechanisms.

Significance Statement: Presynaptic Nrg1 to post-synaptic ErbB signaling contributes to excitatory synapse formation and plasticity, and disturbances in this signaling are thought to contribute to a number of structural and functional endophenotypes associated with schizophrenia. In this study we uncover a new role for axonal Nrg1 signaling in the formation and functional maturation of glutamatergic, pre-synaptic specializations. Axonal signaling by Nrg1 adds an additional layer of complexity to the role of these molecules in neuronal development and might provide additional insight into their contribution to the etiology of schizophrenia.