Figure 4.

Schematic representation of potential interactions between the thyroid and GABA and the GABA catabolic pathway. Enzymes represented numerically: E1 and E2, glutaminase and glutamine synthetase; E3, glutamic acid decarboxylase; E4, GABA‐transaminase; E5, succinic semialdehyde dehydrogenase, site of the defect in patients with SSADH deficiency (crossed‐hatched box); and E6, aldo‐keto reductase 7a2. Additional abbreviations: GABA, γ‐aminobutyrate; GHB, γ‐hydroxybutyrate; TRH, thyrotropin releasing hormone; TSH, thyroid stimulating hormone; T₃, liothyronine; T₄, thyroxine. Plus (+) and minus (−) symbols refer to stimulation and inhibition, respectively. GABA is believed to downregulate thyroid activity at all levels of the hypothalamic‐pituitary‐thyroid endocrine axis, most likely effected via vagal innervation. Changes in plasma T₃/T₄ appear to differentially stimulate or depress GABAergic systems in brain and thyroid gland. Both GABA and GHB are elevated in brain of SSADH‐deficient patients and null mice. Plasma GABA concentrations did not correlate with circulating TSH (not shown). Also shown in the brain are the use‐dependent effects of GABA and GABA_B subunit expression, as demonstrated in thalamus and hippocampus of SSADH‐deficient mice.9, 10 Downregulation of both receptor subtypes has been confirmed as well in SSADH‐deficient patients. (Figure adapted from Ref. 15). GHB, gamma hydroxybutyric acid; GABA, gamma‐amino butyric acid.