Implications for treatment: GABAA receptors in aging, Down syndrome and Alzheimer’s disease

• Published in: Journal of neurochemistry 2011-05, Vol.117 (4), p.613-622
• Main Authors: Rissman, Robert A., Mobley, William C.
• Format: Article
• Language: English
• Subjects: age; Aging; Aging - physiology; Alzheimer Disease - drug therapy; Alzheimer Disease - metabolism; Alzheimer Disease - physiopathology; Alzheimer's disease; Animals; Biological and medical sciences; Central Nervous System - metabolism; Central Nervous System - physiology; Chromosome aberrations; Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases; Down syndrome; Down Syndrome - drug therapy; Down Syndrome - metabolism; Down Syndrome - physiopathology; Excitatory Amino Acids - physiology; GABA Agents - therapeutic use; GABA receptor; GABAA; Humans; Medical genetics; Medical sciences; Neurochemistry; Neurodegeneration; Neurology; Receptors, GABA-A - metabolism; Receptors, GABA-A - physiology; seizure
• ISSN: 0022-3042; 1471-4159
• DOI: 10.1111/j.1471-4159.2011.07237.x

J. Neurochem. (2011) 117, 623–631. In addition to progressive dementia, Alzheimer’s disease (AD) is characterized by increased incidence of seizure activity. Although originally discounted as a secondary process occurring as a result of neurodegeneration, more recent data suggest that alterations in excitatory‐inhibitory (E/I) balance occur in AD and may be a primary mechanism contributing AD cognitive decline. In this study, we discuss relevant research and reports on the GABAA receptor in developmental disorders, such as Down syndrome, in healthy aging, and highlight documented aberrations in the GABAergic system in AD. Stressing the importance of understanding the subunit composition of individual GABAA receptors, investigations demonstrate alterations of particular GABAA receptor subunits in AD, but overall sparing of the GABAergic system. In this study, we review experimental data on the GABAergic system in the pathobiology of AD and discuss relevant therapeutic implications. When developing AD therapeutics that modulate GABA it is important to consider how E/I balance impacts AD pathogenesis and the relationship between seizure activity and cognitive decline.