Glutamate receptor δ1 induces preferentially inhibitory presynaptic differentiation of cortical neurons by interacting with neurexins through cerebellin precursor protein subtypes

Glutamate receptor (GluR) Iδ1 is widely expressed in the developing forebrain, whereas GluRIδ2 is selectively expressed in cerebellar Purkinje cells. Recently, we found that trans-synaptic interaction of postsynaptic GluRIδ2 and pre-synaptic neurexins (NRXNs) through cerebellin precursor protein (Cbln) 1 mediates excitatory synapse formation in the cerebellum. Thus, a question arises whether GluRIδ1 regulates synapse formation in the forebrain. In this study, we showed that the N-terminal domain of GluRIδ1 induced inhibitory presynaptic differentiation of some populations of cultured cortical neurons. When Cbln1 or Cbln2 was added to cultures, GluRIδ1 expressed in HEK293T cells induced preferentially inhibitory presynaptic differentiation of cultured cortical neurons. The synaptogenic activity of GluRIδ1 was suppressed by the addition of the extracellular domain of NRXN1α or NRXN1β containing splice segment 4. Cbln subtypes directly bound to the N-terminal domain of GluRIδ1. The synaptogenic activity of GluRIδ1 in the presence of Cbln subtypes correlated well with their binding affinities. When transfected to cortical neurons, GluRIδ1 stimulated inhibitory synapse formation in the presence of Cbln1 or Cbln2. These results together with differential interactions of Cbln subtypes with NRXN variants suggest that GluRIδ1 induces preferentially inhibitory presynaptic differentiation of cortical neurons by interacting with NRXNs containing splice segment 4 through Cbln subtypes. Precise synaptic connections between neurons in the brain provide the basis of perception, learning, memory and cognition. Trans-synaptic interaction of glutamate receptor (GluR) Iδ2 and neurexins (NRXNs) through cerebellin precursor protein (Cbln) 1 mediates excitatory synapse formation in the cerebellum. Here, we show that GluRIδ1 preferentially induces inhibitory pre-synaptic differentiation of some populations of cortical neurons by interacting with NRXNs through Cblns.