During development of the vertebrate central nervous system (CNS), enormous numbers of various neurons need to be precisely interconnected to exert elaborate neural function. Formation, maintenance, and impairment of synaptic connections in the CNS have been extensively studied. On the other hand, little attention has been paid for the location of synaptic connections. The vertebrate retina, a part of the CNS, provides us with a useful model system for the analysis of neural network development that depends on genetic information. The retinal neural circuits are assembled of five types of neurons and one type of glial cell, forming three distinct layers: the outer nuclear layer (ONL), the inner nuclear layer (INL), and the ganglion cell layer (GCL). Retinal axons and dendrites form synapses in two plexiform layers: the outer plexiform layer (OPL) and the inner plexiform layer (IPL), which separate the nuclear layers. In the OPL photoreceptor terminal contacts with bipolar and horizontal cell processes. Bipolar, amacrine, and ganglion cell terminals form synapses in the IPL.
In order to study the determination mechanisms of the synaptic positions especially in the OPL, we searched genes which highly expressed in the photoreceptor cells and are predictable as a synapse component. We identified a membrane cytoskeletal protein gene as a one of synaptic positional determinant candidates from the microarray analyses with retinal-Otx2 conditional knockout mice which convert photoreceptor cells to amacrine-like cells, thus have non-photoreceptor cell retina.
We found that the membrane skeletal protein is predominantly expressed in rod photoreceptor cells in the retina. This mutant mice showed an aberrant localization of photoreceptor terminal in the ONL. Although photoreceptor synapses normally connect with bipolar and horizontal cell terminals, OKR analysis exhibited impaired visual responses in the membrane cytoskeletal protein deficient mice. Our study implies that the synapse location has a biological sense in the neural circuit.