Functional differences between D1 and D5 revealed by high resolution imaging on live neurons

The interaction between the dopaminergic and glutamatergic systems governs normal behavior and is perturbed in many psychiatric disorders including schizophrenia. Hypofunction of the D1 family of receptors, to which the D1 and D5 subtypes belong, is a typical feature of schizophrenia. Here we have used confocal live cell imaging of neurons to examine the distinct roles of the D1 and D5 receptors in the intra-neuronal interaction with the glutamatergic system. Using fluorescently tagged D1 or D5 expressed in cultured striatal neurons, we show that both receptor subtypes are primarily transported via lateral diffusion in the dendritic tree. D1 is to a much larger extent than D5 expressed in spines. D1 is primarily expressed in the head whereas D5 is largely localized to the neck of the spine. Activation of N-methyl-d-aspartic acid (NMDA) receptors slowed the diffusion rate and increased the number of D1 positive spines, while no effect on D5 diffusion or spine localization could be observed. The observed differences between D1 and D5 can be attributed to structural differences in the C-terminus and its capacity to interact with NMDA receptors and PSD-95. Identification of a unique role of D1 for the intra-neuronal interaction between the dopaminergic and glutamatergic systems will have implications for the development of more specific treatments in many neuropsychiatric disorders.