Involvement of Glutamate in Physiological and Pathophysiological Processes

1. Involvement of Glutamate in Physiological and Pathophysiological Processes

2. Physiology Neuronal synaptictransmission Learning andmemory Development Plasticity Pathology Epileptogenesis Acute neuropathology Hypoxia/Ischaemia Stroke Trauma Chronic neuropathology Alzheimer‘s disease Huntington‘s disease Parkinson‘s disease COOH CH2 CH2 CH H2N COOH Glutamate is Involved in Physiological and Pathophysiological Processes Glutamate

3. NMDA Receptor and Synaptic Plasticity + - Ca2+ levels reach threshold leading to stabilization of plasticity (LTP) Depolarisation removes Mg 2+ block of NMDA receptors Intracellular Ca2+ levels increase Na + flows leads to partial depolarisation Ca2+ flows through NMDA channels Relevant signal arrives Glutamate is released and binds to NMDA & AMPA receptors Na+ flows through AMPA rec. - NMDA rec. remain blocked by Mg2+ - + Danysz and Parsons, Int J Geriatr Psychiatry 2003

4. Glutamatergic and Cholinergic Transmission e.g. NBM Choline + acetate Glia AChE Neuron 1 Neuron 2 Neuron 3 Choline + acetate Glia AChE Glutamate NMDA ACh Acetylcholinesterase Glutamate uptake ACh receptor Ca2+ Parsons and Danysz, unpublished

5. Channel BlockersMg2+Memantine AntagonistsSelfotelMRZ 2/576Ifenprodil (2B)Zn2+ ModulatorsPolyamines Histamine AgonistsGlutamate NMDA CoagonistGlycine D-serine The NMDA Receptor Parsons et al., Drug News Perspect 1995

6. Energy deficit • Decreased glutamate uptake • Increased glutamate release • Decrease in membrane potential • Loss of Ca2+ homeostasis Glutamate as an excitotoxin Ca2+as a mediator of cell death Glutamate – When a Transmitter Turns into a Neurotoxin Glutamate as a mediator of physiological functions Ca2+as a second messenger Müller et al., Pharmacopsychiatry 1995

7. 3 -Amyloid 4 5 -Amyloid Induced Disturbance ofSynaptical Glutamate Homeostasis 1 APP Ca2+ - + 2 1 Furukawa et al. (1998) Masliah et al. (1998) Mattson et al. (1993)Wu et al. (1995) Noda et al. (1999) Harris et al. (1996) Glu 2 T - + 3 + Glu 4 Glia 5 Danysz and Parsons, unpublished

8. NMDA Receptor : a common Target Downstream of Converting Insults Inflammation ß-amyloid NMDA receptor Metabolic compromise Danysz and Parsons, unpublished

9. Alzheimer’s Disease Neuronal death following chronic insult Cognitive deficit due to a decrease in signal to noise ratio Hypothesis of increased “noise” at glutamatergic synapses Energy deficit, increased glutamate levels etc. lead to a tonic mild activation of NMDA receptors

10. Pathological activation of NMDA receptors Impairment of plastic processes Chronic neurodegeneration rest learning Ca2+ Ca2+ Ca2+ signal not detected damaged neurons Glutamate Magnesium signal noise noise Neurodegenerative Dementia Danysz et al., Neurotox Res 2000