Neurobiology of Aging 27 (2006) 1110–1117 Involvement of the GABAergic system in depressive symptoms of Alzheimer’s disease Monica Garcia-Alloza a,1 , Shirley W. Tsang b,1 , Francisco J. Gil-Bea a,1 , Paul T. Francis c , Mitchell K. Lai c,d , Beatriz Marcos a , Christopher P. Chen b , Mar´ ıa J. Ramirez a,∗ a Department of Pharmacology, School of Medicine, Center for Applied Medical Research, University of Navarra, Irunlarrea 1, 31008 Pamplona, Spain b Department of Neurology, Singapore General Hospital, Singapore c Dementia Research Laboratory, Wolfson Centre for Age-Related Diseases, GKT School of Biomedical Sciences, King’s College, London, UK d Department of Clinical Research, Singapore General Hospital, Singapore Received 13 December 2004; received in revised form 4 May 2005; accepted 1 June 2005 Available online 5 July 2005 Abstract Cognitive and neuropsychiatric (BPSD) symptoms seen in Alzheimer’s disease (AD) probably result from differential neurotransmitter alterations. The involvement of the glutamatergic and GABAergic system in cognitive and behavioral and psychological symptoms of dementia (BPSD) has been studied in post-mortem frontal and temporal cortex from AD patients who had been prospectively assessed with the Mini- Mental State Examination (MMSE) for cognitive impairment and with the Present Behavioral Examination (PBE) for BPSD. In addition to cholinergic deficits, significant decreases in -amino butyric acid (GABA) content, with no changes in glutamate content, were found in frontal and temporal cortex. Both GABA levels and the glutamate/GABA ratio showed significant correlations with depression in AD. In the temporal cortex, higher densities of GABA A /benzodiazepine receptors also correlated with more severe depression. It can be suggested that in a situation of cholinergic deficit, such as AD, an imbalance between the excitatory glutamatergic tone and inhibitory GABAergic tone may be responsible for non-cognitive behavioral disturbances. © 2005 Elsevier Inc. All rights reserved. Keywords: Cognitive deficit; Behavioral and psychological syndromes of dementia (BPSD); GABA; Cortex; Glutamate; GABA A receptors; GABA B receptors; Benzodiazepine receptors; Choline acetyltransferase (ChAT) 1. Introduction Alzheimer’s disease (AD) is a chronic progressive disor- der characterised by dementia but often featuring behavioral and psychological syndromes referred to as behavioural and psychological symptoms of dementia (BPSD, [23]). It is increasingly clear that these symptoms are not simply a con- sequence of cognitive impairment, but probably result from distinct neurotransmitter dysfunction. It is therefore, impor- tant to understand the neurochemical basis of the pathophysi- ology of AD to allow the development of rational therapeutic approaches for these troublesome symptoms. Neurochem- ∗ Corresponding author. Tel.: +34 948425600; fax: +34 948425649. E-mail address: mariaja@unav.es (M.J. Ramirez). 1 These authors contributed equally to the present work. ically, the classical hallmark of AD is the disruption of basal forebrain cholinergic pathways and consequent cortical cholinergic denervation of the neocortex and hippocampus. This cholinergic dysfunction, together with glutamatergic deficits, is considered to underlie cognitive disturbance of AD [16,17,42,54]. Deficiencies in central noradrenergic [33], serotonergic [7,8,18], and perhaps dopaminergic [52] but see also [37] neural transmission may also play a critical role in some of the clinical manifestations of AD, particularly BPSD. Significant reductions in -amino butyric acid (GABA) levels have been described in more severe cases of AD but clinical correlates of these changes have not previously been reported [32,45]. The extent and nature of BPSD in AD is varied and includes aggressive behavior, overactivity, depression or psychosis [22] all of which are major contributory factors 0197-4580/$ – see front matter © 2005 Elsevier Inc. All rights reserved. doi:10.1016/j.neurobiolaging.2005.06.003