With medical advancements extending the life span, age-related cognitive decline is a growing problem for the United States. A rat model of cognitive aging was used to investigate the GABAergic neurotransmitter system in relation to changes in learning and memory functions. Confocal stereology was used to determine the number of GABAergic and cholinergic projection neurons in the rostral basal forebrain of spatially characterized young and aged male F344 rats. The GABAergic system was then assessed as a potential target for improving age-related cognitive decline using an odor discrimination task sensitive to decline in aging. Performance of aged rats was impaired compared to young rats on the spatial version of the Morris water maze. Notably, a high degree of variability in individual abilities was observed among aged rats such that some aged rats performed on par with young (aged-unimpaired) and others performed outside the range of young, demonstrating impairment (aged-impaired). The number of basal forebrain neurons expressing multiple immunomarkers for GABAergic septohippocampal projection cells was selectively increased in aged-impaired rats in comparison to both young and aged-unimpaired rats. Indeed, among aged rats, worse performance in the water maze was reliably associated with higher GABAergic cell number. The number of cholinergic neurons, quantified in adjacent sections did not differ as a function of chronological age or cognitive status. These data suggest that aging can dysregulate GABAergic systems in circuitry important for learning and memory and such alterations may contribute to age-related cognitive decline. To test whether the GABAergic system may be a viable target for treating age-related cognitive decline, a second cohort of young and aged rats was characterized in an odor discrimination task. Similar to aged rat water maze performance, some aged rats performed odor learning discrimination problems on par with the young cohort (i.e. aged-unimpaired) and some aged rats were impaired compared to young (i.e. aged-impaired). Using a within-subjects design, the GABA(B) antagonist, CGP 55845 completely ameliorated odor discrimination learning deficits in aged-impaired rats in a dose-dependent manner. These data support the hypothesis that the GABAergic system should be a novel target for therapies aimed at treating age-related cognitive decline.

There is an increasing interest in studying the concentration of the inhibitory neurotransmitter γ-Amino Butyric Acid (GABA), both in the healthy and diseased brain by using Magnetic Resonance Spectroscopy (MRS). Recent studies have shown correlations between an abnormal GABA concentration in certain regions of the brain and disorders as e.g. Parkinson’s disease and depressive disorders. There are presently many technical difficulties with the absolute quantification of GABA and the method MEGA-PRESS is currently the standard technique used in data acquisitions and processing of spectra. In this thesis, different techniques of GABA quantification have been evaluated and the most important aspect was to explore the precision of the method for further usage as a clinical tool. This project involved the exploration of data acquisitions by using a MEGA-PRESS sequence on a 3 T MR-system, processing of the resulting datasets using different methodologies, GABA quantification by using linear combination of model spectra (LCModel), and interpretation of the results by performing statistical analyses. The thesis resulted in a low resolution GABA-atlas of the brain which did not indicate any significant differences in the GABA concentration within the healthy subject group. However, a significant regional difference was observed in the brain. The main uncertainties arose mainly due to the relatively small subject groups and the large measurement error. Future measurements will require improvements both in the data acquisition and in analyzing these with an improved method of processing. The final conclusion was that the GABA quantification sequence MEGA-PRESS is useful both in diagnosis and as a research tool, although further improvements are required.

Thesis (Ph. D.)--Hong Kong University of Science and Technology, 2002. / On t.p. "A̳" is subsript. Includes bibliographical references (leaves 160-177). Also available in electronic version. Access restricted to campus users.

Thesis (Ph. D. (Biochemistry))--Rhodes University, 2003.

The etiology and pathophysiology of schizophrenia are poorly understood, although increasing evidence suggests an important role for altered GABA neurotransmission. Animal models of schizophrenic symptoms include administration of noncompetitive N-methyl-D-aspartate (NMDA) glutamate receptor antagonists, such as dizocilpine (MK-801), and post-weaning social isolation. The present study tested the hypothesis that a “double-hit” model, in which subchronic MK-801 administration and post-weaning social isolation are combined, produces greater behavioural and neurochemical effects than either insult alone. As a secondary objective, the present study also assessed whether the timing of the subchronic MK-801 injections (early adolescence vs. early adulthood) influences these measures. Male Sprague-Dawley rats (N = 74) were obtained at weaning (P21) and were either socially isolated (n = 42) or group housed (n = 32) for the duration of the experiment. Subgroups received subchronic treatment with MK-801 (0.5 mg/kg ip) or saline injections (1.0 ml/kg ip) twice daily for seven days either during early adolescence (P25-P32) or early adulthood (P56-63). At P70, all groups were tested for locomotor activity and subsequently sacrificed to assess the function of the GABA membrane transport protein, GAT-1, and GABAA receptor expression in the frontal cortex and hippocampus. For animals treated in early adulthood, post-weaning social isolation, in comparison to group housing, resulted in an increase in (1) locomotor activity (2) GAT-1 activity in frontal cortex and hippocampus and (3) GABAA receptor expression in the frontal cortex. MK-801 treatment in early adulthood increased GABAA receptor expression in the hippocampus, whereas post-weaning social isolation had no effect on GABAA receptor expression in the hippocampus. Previous studies have demonstrated that increased GAT-1 activity is associated with suppression of GABA-mediated inhibitory synaptic transmission. Furthermore, increased GABAA receptor expression may be a compensatory response to decreased availability of GABA. These data indicated that combined post-weaning social isolation and subchronic MK-801 treatment do not produce additive or synergistic effects on locomotor behaviour or GABA signalling, but rather induced differential effects on GABAA receptor binding. / Thesis (Master, Neuroscience Studies) -- Queen's University, 2010-09-01 15:21:58.474

Zugl.: München, Univ., Diss., 2007

Thesis (M. Phil.)--Hong Kong University of Science and Technology, 2004. / Includes bibliographical references (leaves 103-113). Also available in electronic version. Access restricted to campus users.

Thesis (M. Phil.)--Hong Kong University of Science and Technology, 2002. / On t.p. "GABAA̳" is subscript. Includes bibliographical references (leaves 63-68). Also available in electronic version. Access restricted to campus users.

Thesis (Ph.D.)--Georgetown University, 2009. / Includes bibliographical references.

On t.p. "A̳" and "2̳" are subscript. Includes bibliographical references (p. [100]-112).