C1 Neurons in the RVLM: are they catecholaminergic in name only? (Commentary on Abbott et al.)

Catecholaminergic neurons in the rostral ventrolateral medulla (RVLM), also known as the C1 cell group, are known to play an important role in the generation and control of sympathetic activity (Card et al., 2006). Many of these C1 neurons, as well as neighboring non-catecholaminergic neurons in the RVLM, monosynaptically project to the intermediolateral column of the spinal cord and provide the primary tonic excitatory drive to sympathetic vasomotor and cardiac neurons (Guyenet et al., 2013). RVLM C1 neurons also send projections to many other centers involved in respiratory and autonomic function including the dorsal vagal motor nucleus (DePuy et al., 2013). Here, in this very comprehensive and interesting study conducted by Abbott et al. (2013), the authors crossbred mice to produce progeny in which dopamine-β-hydroxylase-containing neurons lacked the glutamate transporter VGLUT2, a transporter responsible for the sequestration of the excitatory neurotransmitter glutamate into synaptic vesicles in these neurons. Furthermore, C1 neurons in these animals could be selectively activated in vivo using optogenetic stimulation of expressed channelrhodopsin-2 (ChR2) following microinjection of a floxed ChR2-expressing virus into the RVLM. Selective photostimulation of the C1 neurons increased respiratory frequency in control animals with unaltered VGLUT2 expression, but in mice with VGLUT2 deficiencies in catecholaminergic neurons the responses upon C1 photoactivation were absent. Similarly, the activation of vagal fibers upon photoactivation of C1 neurons was blunted or absent in animals with VGLUT2 deficiencies. This work, taken together with previous work from this group and others, indicates that catecholaminergic neurons in the RVLM use glutamate primarily, if not exclusively, as a transmitter to influence downstream autonomic and respiratory neurons (Morrison, 2003; Guyenet et al., 2013). This well-founded conclusion raises the issue, are these neurons catecholaminergic in name only? Three potential unexplored roles for catecholamine synthesis in these neurons are that catecholamines are co-released from the synapses of these neurons but do not act on their anticipated postsynaptic neuronal targets but rather alter glial or other non-neuronal targets. Alternatively, catecholamines might only be synaptically co-released from these neurons upon challenges to the autonomic and/or respiratory systems or in disease states. This, while possible, seems unlikely as these investigators stimulated C1 neurons with a range of activation paradigms. Another interesting and yet untested hypothesis is that catecholamines are released not at the synapse but at the soma or dendrites of C1 neurons to serve in a role distinctly different from fast neurotransmission (Sevigny et al., 2008). This important study demonstrates the powerful influence of the glutamatergic projections of these C1 neurons on respiratory and autonomic function, but why they are catecholaminergic remains unknown.

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