Glutamatergic neurotransmission involves glutamate, the major excitatory neurotransmitter in the brain. There are two pathways for glutamate synthesis from precursors and multiple receptor types including NMDA, AMPA, KA, and metabotropic receptors. The different receptor subunits provide diversity in function. Glutamate signaling is involved in many brain pathways and clinical implications include roles in schizophrenia, Parkinson's disease, and drug mechanisms of action.

1. Glutamatergic Neurotransmission Srinath G N N Rao

2. Outline Chemistry Pathways Clinical implications

3. Chemistry GSNAT EAAT

4. Two precursors for glutamate synthesis: α-ketoglutarate , glutamine α-ketoglutarate L-Glutamate GDH

5. Glutamate Receptor Composition Out In Subunits { NMDAR1 NMDAR2a NMDAR2b NMDAR2c Na++ NMDA K+ Ca++ { GLUR1 GLUR2* GLUR3 GLUR4 Ca++ AMPA Na++ K+ Na++ { GLUR5 GLUR6 GLUR7 KA1 KA2 KA K+ Ca++

6. AMPA receptor functional diversity Mixing and matching of subunits (see GABA receptors for examples) Further diversity generated by alternative splicing, editing Flip and flop splice forms desensitize at different rates, both have rapid onset kinetics (gluR2 homomers shown)

8. Ion selectivity is modulated by RNA editing Kandel, Schwartz, Jessel (2000) Principles of Neural Science 4ed

9. NMDAR

10. Co-incidence detection

11. PSD Silent synapse

12. Metabotropic Glutamate Receptors (mGluR’s) mGluR function: modulatory Class C GPCR, very limited homology to rhodopsin mGluR’s are sub-divided based on sequence similarity Group I ( mGluR1 and mGluR5 )(Gq---PLC) Group II ( mGluR2 and mGluR3 )(Gi---AC) Group III ( mGluR4, mGluR6, mGluR7 and mGluR8 )(Gi---AC)

14. Allosteric

15. Positive modulator enhances response to glutamate

16. Negative modulator suppresses response to glutamateModified : http://www.npsp.com/img/img_mGluR_diag.jpg

17. mGlu5 receptor antagonists exhibit the widest and most robust anxiolytic activity (MPEP (2-methyl-6-(phenylethynyl)-pyridine), a highly selective and brain-penetrant mGlu5 receptor antagonist) metabotropic glutamate receptor type 5 with the neuronal Ca2+-binding protein 2 modulates receptor function. activation of either mGlu(5) by positive allosteric modulators or stimulation of mGluR(2/3) receptors by agonists may offer new strategy in schizophrenia treatment.

18. mGlu7 receptor is prominently expressed in the basal ganglia, its role in restoring motor function in animal models of Parkinson's disease are being tried selective mGlu3 receptor agonists or enhancers are potential candidates as neuroprotective agents in Parkinson's disease, and their use might circumvent the limitations associated with the administration of exogenous GDNF.

19. Glycine

20. Glycine- from Choline and L-Serine L-Serine Glial cells L-Serine Glycine L-Serine D-Serine D-Serine OH pyruvate LSerT Glial cell SHMT AMPA Na+ THF Racemase Gly DAO GlyT1 3Na+

22. Pathways in the brain

23. Cortico-brainstem Mesolimbic Pathway

24. Cortico-brainstem Mesocortical Pathway

25. CSTC Loop

26. Dopamine and Glutamate

27. Serotonin and Glutamate

28. Glutamate excitotoxicity

29. Glutamate and Schizophrenia

30. Glutamate and Schizophrenia

31. Miscellaneous Estrogen increases glutamate release Serotonin increases glutamate release

32. Drugs Memantine-gating of blocked channels and binding to two sites on NMDA receptors PCP Ketamine Topiramate-inhibition of GluR5 kainate receptors could represent a key mechanism underlying the anticonvulsant activity of TPM Drugs in schizophrenia- Glutamate agonists or antagonists? Glycine agonists- d- cycloserine

33. References Kaplan & Saddock- CTP 9th ed. Psychopharmacology- Stephen Stahl Psychiatry- Tasman- 3rd ed. Neuroscience- Purves www. Pubmed.com

34. Thank you