Of apples and oranges: GABA and glutamate transmission in neurones of the nucleus tractus solitarii could not be more different

The nucleus tractus solitarii (NTS) is the principal visceral sensory nucleus in the brain and comprises neurochemically and biophysically distinct neurons located in the dorsomedial medulla oblongata. The NTS conveys information from the gustatory, cardiorespiratory, oesophageal and subdiaphragmatic gastrointestinal visceral systems that is subsequently assimilated with homeostatic signals arriving from an impressive network of connections from other integrative centres of the pons, diencephalon and forebrain. Myelinated A-type and unmyelinated C-type sensory afferent fibres from the trigeminal, facial, glossopharyngeal and vagus nerve form the tractus solitarius (TS) and their terminals overlap along the rostro-caudal extent of the NTS. Regardless of their origin or type, though, afferent fibres entering the brainstem activate NTS neurones via the release of excitatory neurotransmitters, mainly glutamate (Andresen & Kunze, 1994; Baptista et al. 2005). Perhaps the most prominent neurochemical phenotypes encountered in the NTS are GABAergic and glutamatergic, which provide postsynaptic inhibitory and excitatory influences to adjacent motor nuclei such as the dorsal motor nucleus of the vagus, the nucleus ambiguus and the ventrolateral medulla. An impressive amount of work has been conducted in recent times by Andresen's group to characterize the glutamatergic transmission from the tractus solitarius onto NTS neurones. This group has used sophisticated electrophysiological analyses to demonstrate that glutamatergic excitatory transmission is highly effective, has an almost unfailing unitary transmission from primary sensory fibres, and can be associated with forms of synaptic plasticity that are unique to autonomic regulation (Peters et al. 2010). Earlier work by Mifflin (Mifflin, 1996; Mifflin & Felder, 1988) and Smith (Smith et al. 1998), however, showed that TS stimulation can evoke a sequence of excitatory responses that were followed by inhibitory currents, indicating the possible presence of a local GABAergic interneurone. This inhibitory interneurone, however, has not yet been demonstrated with anatomical tools. (Note that the presence of GABAergic neurons within the NTS is not in doubt. What remains to be confirmed, however, is the anatomical proof of their interneurone status, i.e. a neurone that does not project beyond the NTS itself.) The publication by McDougall and Andresen (2012) in this issue of The Journal of Physiology utilises an isolated horizontal brainstem slice in which TS fibres can be stimulated to evoke unitary currents in second order NTS neurones; these currents can then be identified as either mono- or polysynaptic. The authors showed that, in contrast to glutamatergic currents, monosynaptic GABAergic currents are evoked by focal stimulation disproportionately rarely and only following a stimulus that was located in close proximity to the recorded neurone. In addition to the high failure rate, large amplitude variability, low calcium sensitivity and modest frequency-dependent depression, the monosynaptic nature of these GABAergic currents was confirmed by a low jitter (albeit greater than that of glutamatergic synapses) and lack of sensitivity to glutamatergic receptor blockade. Overall, these data suggest rather weak GABAergic transmission whose efficacy must rely on converging activation of inhibitory fibres. These characteristics suggest strongly that the GABA release properties are fundamentally different from the powerful and synaptically reliable glutamatergic inputs impinging onto NTS neurones. When taken together with previous observations reporting that each TS-driven glutamatergic input targets individual NTS neurons selectively, and that the physiological and pharmacological responses of NTS neurones are target-coded (Bailey et al. 2006; Browning et al. 2011; Jin et al. 2004), the overall picture of the NTS strengthens the image of a hyperorganized nucleus with ‘task matching’ capabilities conferring an ability to cope with widely variable demands, both in terms of timing as well as duration and modulation of a response. Furthermore, this type of cellular organization within the NTS should force us, once again, to be extremely cautious in the often simplistic physiological interpretation of observations, often driven by high intensity stimuli, that analyse a single outcome such as cFos expression or calcium oscillations, which provide limited information regarding the excitability of neurones and provide no information at all regarding inhibitory transmission. Several questions remain to be answered before one can elucidate the role of these synaptic connections. For example, what are the inputs that activate these second order GABAergic neurones? What is their origin? Are they anatomically defined interneurones, or do they project beyond the NTS? Are they related to a particular pathway? Do they have a specific physiological role or are they ‘simply’ a low pass filter for excitatory TS-driven inputs?