Retrograde Messengers between Nerve Cells

Nitric oxide (NO) is a relatively newly discovered neurotransmitter that may play a role in long-term potentiation (LTP). LTP is a form of synaptic plasticity considered to be linked with learning and memory in the mammalian central nervous system. This is achieved when glutamate, released from a presynaptic terminal, binds to two types of glutamate receptors, N-methyl-D-aspartate (NMDA) and AMPA subtypes.

When sufficient depolarization occurs by activation of AMPA receptors, the Mg2+ that blocks NMDA receptor activity is removed and allows for influx of Ca2+, Na+ and K+ via the NMDA receptors. In particular, Ca2+ binds to the intracellular calmodulin, and activates the enzyme, NO synthase (NOS). The newly generated NO is thought to diffuse out to the presynaptic and/or other surrounding neurons. In this way, NO may operate as a retrograde messenger M that is going back to the presynaptic cell from the postsynaptic cell, causing the presynaptic cell to increase the release of neurotransmitter. This results in strengthened synaptic connections leading to putative learning and memory. We therefore sought to determine the validity of this hypothesis by examining whether the NMDA receptor and NOS are localized in the same postsynaptic neuronal process.

Dual immunocytochemical labeling was performed on adult rat visual cortical sections. Immunocytochemistry technology uses antibodies to detect antigens in intact tissues at cellular and subcellular levels of resolution.

Results so far have shown that dual labeling does exist in the postsynaptic dendrites as the LTP model indicates. Also, there are dual labelings of NOS and NMDA on neuornal cell bodies. Not all cases of NMDA labeling are on the terminals or membrane. There are NMDA stainings on the dendrites and cell bodies deep into the processes or cells, away from the membrane. There is also singly labeled NOS on dendrites, without the presence of NMDA. In these cases, NOS may be activated following the rise in the Ca2+ mediated through voltage-dependent calcium channels or intracellular calcium storage, instead of NMDA receptor activation. These data gathered so far support the idea that NO may play an important role as a retrograde messenger in LTP.

In the future, it would be interesting to determine the precise mechanisms of how retrograde messengers regulate the vesicles and channels, thus controlling the release of neurotransmitters. Besides NO, other diffusable substances, such as CO, may also modulate synaptic plasticity. It would be fascinating to find out their roles and the pathways in which these messengers are formed.