Hippocampal GABAergic synapses possess the molecular machinery for retrograde nitric oxide signaling

Nitric oxide (NO) plays an important role in synaptic plasticity as a retrograde messenger at glutamatergic synapses. Here we describe that, in hippocampal pyramidal cells, neuronal nitric oxide synthase (nNOS) is also associated with the postsynaptic active zones of GABAergic symmetrical synapses terminating on their somata, dendrites, and axon initial segments in both mice and rats. The NO receptor nitric oxide-sensitive guanylyl cyclase (NOsGC) is present in the brain in two functional subunit compositions: alpha(1)beta(1), and alpha(2)beta(1). The beta(1) subunit is expressed in both pyramidal cells and interneurons in the hippocampus. Using immunohistochemistry and in situ hybridization methods, we describe that the a, subunit is detectable only in interneurons, which are always positive for alpha(1) subunit as well; however, pyramidal cells are labeled only for beta(1) and alpha(2) subunits. With double-immunofluorescent staining, we also found that most cholecystokinin- and parvalbumin-positive and smaller proportion of the somatostatin- and nNOS-positive interneurons are a, subunit positive. We also found that the a, subunit is present in parvalbumin- and cholecystokinin-positive interneuron terminals that establish synapses on somata, dendrites, or axon initial segments. Our results demonstrate that NOsGC, composed of a, alpha(1) subunits, is selectively expressed in different types of interneurons and is present in their presynaptic GABAergic terminals, in which it may serve as a receptor for NO produced postsynaptically by nNOS in the very same synapse.