Postsynaptic glutamate receptor δ family contributes to presynaptic terminal differentiation and establishment of synaptic transmission

Synaptic adhesion molecules such as neuroligin are involved in synapse formation, whereas ionotropic transmitter receptors mediate fast synaptic transmission. In mutant mice deficient in the glutamate receptor delta 2 subunit (delta 2), the number of synapses between granule neurons (GNs) and a Purkinje neuron (PN) in the cerebellum is reduced. Here, we have examined the role of delta 2 in synapse formation using culture preparations. First, we found that the size and number of GN presynaptic terminals on a PN in the primary culture prepared from knockout mice were smaller than those in control culture. Next we expressed delta 2 in nonneuronal human embryonic kidney (HEK) cells and cocultured them with GNs. Punctate structures expressing marker proteins for glutamatergic presynaptic terminals were accumulated around the HEK cells. Furthermore, HEK cells expressing both delta 2 and GluR1, a glutamate receptor subunit forming a functional glutamate- gated ion channel, showed postsynaptic current. Deletion of the extracellular leucine/isoleucine/valine binding protein (LIVBP) domain of delta 2 abolished the induction ability, and the LIVBP domain directly fused to a transmembrane sequence was sufficient to induce presynaptic differentiation. Furthermore, a mutant GluR1 whose LIVBP domain was replaced with the delta 2 LIVBP domain was sufficient by itself to establish synaptic transmission. Another member of delta glutamate receptor family delta 1 also induced presynaptic differentiation. Thus, the delta glutamate receptor subfamily can induce the differentiation of glutamatergic presynaptic terminals and contribute to the establishment of synaptic transmission.