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  • By contrast pentameric glycine receptors GlyR

    2022-07-06

    By contrast, pentameric glycine receptors (GlyR) in humans have four functional subunits, α1− α3 and β (Lynch, 2004) whereas the retina of other mammals have an additional α4 subunit (Harvey et al., 2000), and in humans the α4 subunit is considered a pseudogene as it lacks the 4th transmembrane domain (Labonne 2016). Glycine receptors strongly mediate inhibitory neurotransmission in the spinal cord and brainstem. Defects in glycinergic neurotransmission can result in a paroxysmal motor disorder in humans, known as hyperekplexia (Andrew and Owen, 1997; Harvey et al., 2008) that can also be mimicked in animal models (Becker et al., 2000, 2002; Mulhardt et al., 1994; Rees et al., 2002, 2001; Shiang et al., 1993). To date, most available immunohistochemical data on the distribution of GABAAR and GlyR in the hypoglossal nucleus is derived from studies in rodents (Fritschy and Mohler, 1995; Sassoe-Pognetto et al., 2000; Triller et al., 1985). Animal studies have shown that there is strong inhibitory control of hypoglossal jnk inhibitors exerted by glycine (Duggan et al., 1973; O’Brien and Berger, 2001) and GABA, (Morrison et al., 2003a, b; Morrison et al., 2002b; Muller et al., 2006; O’Brien and Berger, 1999, 2001) and the presence of subunits for both GABAA and glycine receptors have been shown in the neonate rat hypoglossal nucleus (Liu and Wong-Riley, 2013; Muller et al., 2006), adult rat (Lorenzo et al., 2006) and in our previous studies in the human hypoglossal nucleus (Waldvogel et al., 2010). The vesicular GABA transporter VGAT has been found to be associated with both GABA and glycinergic terminals and both types of receptors (Benarroch, 2011; Dumoulin et al., 1999) and has been used extensively as a marker for inhibitory terminals. Care must be taken with interpretation of receptor localization in the hypoglossal nucleus as several studies show development changes in the inhibitory receptors from neonate to adult hypoglossal nucleus neurons (Muller et al., 2006, 2004; Sunagawa et al., 2017). In our previous studies on the human brainstem we showed preliminary evidence for the presence of GABAA receptor α1, α2, α3, β2,3 and γ2 subunits and glycine receptors on neurons in the human hypoglossal nucleus (Baer et al., 2003; Waldvogel et al., 2010). In the present study we investigated in further detail to what extent α1, α2,  β2,3 GABAA receptor subunits were colocalised with glycine receptors on hypoglossal neurons in the human brain and to what extent they are associated with the GABA/Glycine transporter VGAT. Physiological studies have shown that GABA and glycine have differing effects on hypoglossal neuron responses which result in different outputs of hypoglossal neurons and the resultant functioning of tongue muscles in a variety of situations, for instance in REM or non REM sleep and breathing (Morrison et al., 2002a, 2002b, 2003a, 2003b; Takata, 1993; ten Bruggencate and Sonnhof, 1972). It is therefore highly important to know the localisation and degree of colocalisation of both GABAA and glycine receptors in order to provide a morphological basis for these physiological functions in the human brain. In addition, the susceptibility of motoneurons to neurological conditions such as ALS is proposed to be dependent on the degree of glycine or GABA innervation or inhibitory receptor composition (Lorenzo et al., 2006). In ALS hypoglossal motoneurons are particularly vulnerable, a loss of glycinergic innervation is considered to be one of the mechanisms responsible for the hyperexcitability and consequent degeneration of motoneurons. Therefore it is vital to know the detailed subunit composition of both GABA and glycine inhibitory receptors on hypoglossal neurons in the human brain.
    Materials and methods
    Results
    Discussion Our previous studies in the human hypoglossal nucleus have shown that at the regional and cellular level, high levels of glycine receptors and moderately high levels of the major GABAA receptor subunits are detected in the hypoglossal nucleus with the highest levels being α and β subunits of glycine receptors.(Baer et al., 2009). The antibodies used were very specific to human receptor subunits as described in the methods, however due to the large number of subunits possible, the correct pentameric subunit composition of GABAA or glycine receptor types in the hypoglossal nucleus is still not possible.