Introduction The hypoglossal nucleus is the nucleus of the

Introduction The hypoglossal nucleus is the nucleus of the twelfth cranial nerve and is located on both sides of the mid line in the dorsal medulla oblongata and is situated between the proximal end of the medullary central canal and the beginning of the fourth ventricle (Tomasch and Etemadi, 1962). In humans the nucleus is approximately 10 mm long and tapers from the dorsal region of the upper medulla at the ponto-medullary junction and extends caudally into the lower medulla. The hypoglossal nucleus contains cholinergic lower motor neurons which innervate tongue muscles. Studies in the rat and primate have shown that the hypoglossal nucleus is divided into two distinct groups based on the innervation of tongue muscles, in particular the main protusor muscle the genioglossus and the main retractor muscles, the hyoglossus, styloglossus and geniohyoid muscles (Kubin, 2016; Lowe, 1981; McClung and Goldberg, 2000; Smith and DeMyer, 2003; Sokoloff and Deacon, 1992). The hypoglossal nucleus and nerve are implicated in the regulation of complex processes which require intricate control of tongue movements involved in respiratory movements, swallowing, mastication and associated tasks such as those related to speech in humans (Connaughton et al., 1986; Lin and Barkhaus, 2009; Roda et al., 2002; Tomasch and Etemadi, 1962). The hypoglossal motor neurons are innervated by multiple inputs including: the hypothalamus, plus a variety of regions throughout the midbrain including; the raphe nuclei, the locus coeruleus subnucleus, the pontine nuclei, and, in the medulla the lateral reticular formation (Kubin, 2016) which all use a variety of transmitter systems (Connaughton et al., 1986; Fung et al., 2001; Rukhadze and Kubin, 2007a, b; Travers, 1995; Zuperku et al., 2008). There is a delicate balance of inhibitory and excitatory inputs that control hypoglossal neuron functions (Takata, 1993). On the inhibitory side, several inputs to the hypoglossal nucleus have been documented. Retrograde labelling of Mirin combined with GAD or glycine immunohistochemistry found they originated from regions within the pontine reticular and medullary reticular formation (Li et al., 1997). Swallowing related inhibitory premotor neurons projecting into the hypoglossal nucleus are located in the regions ventrolateral to the nucleus tractus solitarius and dorsomedial to the nucleus ambiguus in the region ventrolateral to the hypoglossal nucleus and Roller nucleus (Ono et al., 1998). Damage to the hypoglossal nucleus can lead to several pathological symptoms, including impairment of swallowing (dysphagia) and speech production (dysarthria) (Sharifullina and Nistri, 2006). In addition, as in Huntington’s disease, adverse respiratory symptoms can result from impaired tongue muscle control, leading to asphyxia (Heemskerk and Roos, 2011). The two most important inhibitory systems in the brainstem use the neurotransmitters gamma-aminobutyric acid (GABA) and glycine and act through ionotropic GABAA and glycine receptors respectively that are located at synaptic and extra-synaptic sites on a variety of brainstem neurons. Inhibitory neurotransmitter receptors for GABA and glycine control neuronal excitability and are vital for normal brain function. GABAA receptors (GABAAR) are heteropentameric chloride ion channels that facilitate fast-response, inhibitory neurotransmission in the mammalian central nervous system and are the most widespread inhibitory receptor type in the central nervous system. GABAAR are pentameric combinations of subunits assembled from a variety of different subtypes including  α1−6, β1−3, γ1−3, δ, ε, θ, π (Mohler, 2007; Olsen, 2008) and, depending on the subunits, are primarily localised on the post-synaptic and extra synaptic membranes of inhibitory synapses in the mammalian brain (Moss and Smart, 2001), but also presynaptically (Engelman and MacDermott, 2004; Kullmann et al., 2005; Rudomin and Schmidt, 1999). Dysfunction of GABAAR responses is a feature of a number of neurological conditions including anxiety, epilepsy and schizophrenia. Many major drugs (e.g. benzodiazepines) act primarily via GABAAR, and extensive research efforts have focused on the GABAAR because of its major role in inhibition in the CNS (Crestani et al., 1999; Loup et al., 2000; Mohler, 2006a, b, 2007; Scheffer and Berkovic, 2003).