The neuregulin (NRG) family of trophic factors is present in the central and peripheral nervous systems and participates in the survival, proliferation, and differentiation of many different cell types, including motoneurons. NRG1 was first characterized by its role in the formation of the neuromuscular junction, and recently it was shown to play a crucial role in modulating glutama-tergic and cholinergic transmission in the central nervous system of adult rats. However, little is known about NRG1's role in adult motor systems. Motoneurons receive dense glutamatergic and cholinergic input. We hypothesized that NRG1 is present at synapses on phrenic motoneurons. Confocal microscopy and 3D reconstruction techniques were used to determine the distribution of NRG1 and its colocalization with these different neurotransmitter systems. We found that NRG1 puncta are present around retrogradely labeled motoneurons and are distributed predominantly at motoneuron somata and primary dendrites. NRG1 is present exclusively at synaptic sites (identified using the presynaptic marker synaptophysin), making up ~30% of all synapses at phrenic motoneurons. Overall, NRG1 immunoreactivity is found predominantly at cholinergic synapses (75% ± 14% colocalize with the vesicular acetylcholine transporter; VAChT). Nearly all (99% ± 1%) VAChT-immunoreactive synapses expressed NRG1. NRG1 also is present at a subset of glutamatergic synapses expressing the vesicular glutamate transporter (VGLUT) type 2 (~6%) but not those expressing VGLUT type 1. Overall, 26% ± 6% of NRG1 synapses are VGLUT2 immunoreactive. These findings provide the first evidence suggesting that NRG1 may modulate synaptic activity in adult motor systems.
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