GABA transporters (GAT-1) in Alzheimer's disease

Nägga, Katarina; Bogdanović, Nenad; Marcusson, Jan

doi:10.1007/s007020050230

Cited by 29 publications

(15 citation statements)

References 39 publications

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“…16 In contrast, biochemical investigations of biopsy brain tissue from patients in the early phases of AD have not shown significant alterations in the concentration of GABA 44,46 and no disturbance of GABA transporters. 47,48 It is possible, therefore, to conclude that the motor cortex hyperexcitability of AD is not caused by the dysfunction of GABAergic intracortical inhibitory circuits. 16,17 Motor programming and execution is based on a distributed network with replicated topographic organization of the same body district (particularly for hand and finger control) which has been considered of importance in motor learning and in functional recovery after partial lesions of the motor brain centers.…”

Section: Discussionmentioning

confidence: 97%

Motor cortex excitability in Alzheimer's disease: A transcranial magnetic stimulation study

Ferreri¹,

Pauri²,

Pasqualetti³

et al. 2002

Annals of Neurology

204

130

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Motor deficits affect patients with Alzheimer's disease only at later stages. Recent studies demonstrate that the primary motor cortex is affected by neuronal degeneration accompanied by the formation of amyloid plaques and neurofibrillary tangles. It is conceivable that neuronal loss is compensated by reorganization of the neural circuitries occurring along the natural course of the disease, thereby maintaining motor performances in daily living. Cortical motor output to upper limbs was tested via motor-evoked potentials from forearm and hand muscles elicited by transcranial magnetic stimulation of motor cortex in 16 patients with mild Alzheimer's disease without motor deficits. Motor cortex excitability was increased, and the center of gravity of motor cortical output, as represented by excitable scalp sites, showed a frontal and medial shift, without correlated changes in the site of maximal excitability (hot-spot). This may indicate functional reorganization, possibly after the neuronal loss in motor areas. Hyperexcitability might be caused by a dysregulation of the intracortical GABAergic inhibitory circuitries and selective alteration of glutamatergic neurotransmission. Such findings suggest that motor cortex hyperexcitability and reorganization allows prolonged preservation of motor function during the clinical course of Alzheimer's disease.

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Section: Discussionmentioning

confidence: 97%

Motor cortex excitability in Alzheimer's disease: A transcranial magnetic stimulation study

Ferreri¹,

Pauri²,

Pasqualetti³

et al. 2002

Annals of Neurology

204

130

View full text Add to dashboard Cite

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“…Indeed, it has been suggested that GABAergic circuits in the cerebral cortex of AD are relatively well preserved when compared with circuits that use other neurotransmitters systems (Young, 1987; Lowe et al, 1988; Reinikainen et al, 1988; Ferrer et al, 1991; Hof et al, 1991; Nägga et al, 1999; Rissman et al, 2007). However, alterations of neurons labeled for parvalbumin were identified in the cerebral cortex of AD patients in several studies (Fonseca et al, 1993; Solodkin et al, 1996; Brady and Mufson, 1997; Mikkonen et al, 1999), which are responsible for most of the GABAergic pericellular innervation of pyramidal cells (basket and chandeliers cells).…”

Section: Discussionmentioning

confidence: 99%

Diminished perisomatic GABAergic terminals on cortical neurons adjacent to amyloid plaques

et al. 2009

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One of the main pathological hallmarks of Alzheimer's disease (AD) is the accumulation of plaques in the cerebral cortex, which may appear either in the neuropil or in direct association with neuronal somata. Since different axonal systems innervate the dendritic (mostly glutamatergic) and perisomatic (mostly GABAergic) regions of neurons, the accumulation of plaques in the neuropil or associated with the soma might produce different alterations to synaptic circuits. We have used a variety of conventional light, confocal and electron microscopy techniques to study their relationship with neuronal somata in the cerebral cortex from AD patients and APP/PS1 transgenic mice. The main finding was that the membrane surfaces of neurons (mainly pyramidal cells) in contact with plaques lack GABAergic perisomatic synapses. Since these perisomatic synapses are thought to exert a strong influence on the output of pyramidal cells, their loss may lead to the hyperactivity of the neurons in contact with plaques. These results suggest that plaques modify circuits in a more selective manner than previously thought.

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“…However, in a recent study in which human APP was expressed in rat hippocampal neurons using a viral expression system, no change in GABAergic transmission was observed, while both AMPA and NMDA receptor-mediated transmission was impaired (Kamenetz et al, 2003). In addition, postmortem studies using AD brain tissue, indicate that GABAergic interneurons are relatively spared (Nagga et al, 1999). Taken together, these studies suggest the overexpression of A␤ has a limited effect of GABAergic interneurons, and this is supported by the findings reported here.…”

mentioning

confidence: 84%

Synaptic transmission and synchronous activity is disrupted in hippocampal slices taken from aged TAS10 mice

et al. 2005

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Synaptic transmission was studied in hippocampal slices from aged (12-14 months of age) TAS10 mice overexpressing the human form of the amyloid precursor protein harboring the Swedish mutation. A significant deficit in the input-output relationship of glutamatergic synapses in the CA3-CA1 Schaffer collateral pathway was observed, while synaptic transmission in the medial perforant pathway of the dentate gyrus was comparatively preserved. Despite this deficit, relative levels of short- and long-term synaptic plasticity in the CA1 region were similar to those observed in wildtype slices. Specifically, paired pulse facilitation, frequency facilitation (at frequencies of 1, 5, and 10 Hz), and long-term potentiation induced by a theta burst stimulation paradigm were all normal in the CA3-CA1 synapses of TAS10 hippocampal slices. However, synchronized network activity induced by bath application of 4-aminopyridine (4-AP) was compromised. Thus, the frequency of synchronous events induced by 100 microM 4-AP was significantly lower in TAS10 hippocampal slices (inter-event interval: WT, 2.4+/-0.6 s; TAS10, 6.9+/-1.7 s). To study gamma-aminobutyric acid (GABA)ergic synaptic transmission NBQX (20 microM) and D-AP5 (50 microM) were added in order to isolate bicuculline-sensitive GABA-mediated synchronous network activity. The GABAergic network activity was not significantly different from wildtype in terms of frequency. This study suggests that the deficit in glutamatergic synaptic transmission observed in the TAS10 hippocampal slices, may be coupled with alterations in synchronous network activity, which in turn would lead to deficient information processing.

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GABA transporters (GAT-1) in Alzheimer's disease

Cited by 29 publications

References 39 publications

Motor cortex excitability in Alzheimer's disease: A transcranial magnetic stimulation study

Motor cortex excitability in Alzheimer's disease: A transcranial magnetic stimulation study

Diminished perisomatic GABAergic terminals on cortical neurons adjacent to amyloid plaques

Synaptic transmission and synchronous activity is disrupted in hippocampal slices taken from aged TAS10 mice

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