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The animation explains the processes involved in normal glutamatergic neurotransmission, in pathological glutamate release and the mechanism of action of memantine in Alzheimer dementia.

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Introduction

The excitatory neurotransmitter glutamate plays an important part in the development of neurodegenerative diseases like dementia. About 70 % of all excitatory synapses in the central nervous system are stimulated by the neurotransmitter glutamate. Dysfunction of glutamatergic neurotransmission is involved in pathomechanism of neurodegenerative dementia. The excitatory effect of chronically released glutamate effects the degeneration of cortical and subcortical neurons, thus leading to the occurrence of dementia symptoms.

Read more about: Glutamate and Dementia – The NMDA-Receptor.

Normal glutamatergic neurotransmission

Under physiological conditions, the NMDA receptor is blocked by magnesium ions, thereby protecting the neuron against glutamatergic excitotoxicity. During physiological learning and memory processes, high concentrations of synaptic glutamate are transiently released. Due to its strong voltage-dependency, magnesium leaves the NMDA receptor. Calcium enters into the cell, and through secondary processes, the signal is recognized. This is clearly discernible behind the low background noise.

Alzheimer dementia

The athological, sustained release of low glutamate concentrations, from both neurones and surrounding glia cells, also displaces magnesium from the NMDA receptor channel. There is a continuous influx of calcium into the cell, increasing the calcium pool. In the case of learning and memory processes, the transient synaptic release of glutamate causes more calcium to flow into the cell. However, due to the already elevated calcium concentration, the signal can no longer be detected (occurrence of dementia symptoms).

In the course of the disease, the chronic release of glutamate and the permanently increased intracellular calcium concentration leads to neuronal degeneration (neurodegeneration).

Sites of action of memantine in dementia

The starting point is the pathological release of glutamate, followed by elevated calcium concentrations. As memantine, in contrast to magnesium, blocks the NMDA receptor in the presence of sustained release of low glutamate concentrations, the influx of calcium is prevented (neuroprotection). The intracellular calcium pool is reduced, and the noise lower. During learning and memory processes (i.e. transient high glutamate release), memantine – the fast, voltage-dependent NMDA-receptor antagonist – leaves the NMDAreceptor for a short time. A signal is produced which due to the lower noise can be recognized and processed which leads to a symptomatic improvement in dementia symptoms.