Brain tissue: ACSF:

5-15 mmol/kg Few μM

Total brain: Inside cells:
Approx. 2.3 g 1-10 mM

Cleft:
Milimolar
(removed in
miliseconds)

GLUTAMATE:
the most abundant neurotransmitter

Bernat González i Llinares

 Functional Role
Fast excitatory
Transmission CNS
 Plasticity
 Cognitive functions
Metabolic Functions
 Energy production
 Ammonia
detoxification
 Protein synthesis
 GABA precursor
From Perea et al., 2009
 Physiology
 Motor control (cortex  spinal cord)
 Learning & Memory (LTP/LTD)
 Pain (dorsal horn of the spinal cord)

 Umami Taste
monosodium glutamate

From Hartsock, 2000

 Pathophysiology
 “Glutamate hypothesis” of Schizophrenia
 Epilepsy
→ HHS (GLUD1 mutation: GDH overactivity)
 Huntigton's disease
 Alzheimer’s disease (mementine)
 Amyotrophic lateral sclerosis (ALS)
→ Riluzole
 Ischemic Stroke: no O2/glucose → no ATP →
ion pumps stop working → EEATs reversed →
EXCITOTOXICITY!
 Pathophysiology

From Maragakis and Rothstein, 2001

 Pathophysiology (cont’d)

 Neuropathic Pain
 Parkinsonism
 Depression/anxiety
 Drug addiction
 Autism
 Multiple Sclerosis
 Etc…
Description of the System
 Distribution

 Cortico-cortical
 Thalamus – cortex
 Extrapyramidal
pathway
(cortex - striatum)
 Cortex, substantia
nigra, subthalamic
nucleus, pallidum
Ubiquitous
 Biosynthesis: transaminase

P

From Nedergaard et al., 2002

Biosynthesis: Glutamate-Glutamine

P

From Nedergaard et al., 2002

 Storage

 VGLUTs
– VGLUT1 & 2 expressed complementary
– VGLUT3 (GABA interneurons & astrocytes)
→ Serotonin, acetylcholine?

From Fremeau et al., 2004

 Storage: VGLUTs distribution

 VGLUTs
 Heterogenous distribution, curiously 3
isoforms expressed in non-glutamatergic
neurons
Serotonin or acetylcholine?
d

From El Mestikawy et al., 2011

 Release

 Exocytotic
– Synchronous or Phasic
(coupled to incoming APs)
– Asynchronous release (delay)
– Spontaneous or Tonic
 Non-Exocytotic (glia)
 Exocytosis

From Ziv & Garner 2004

 Exocytosis (simplified)

– Synchronous/Phasic
(coupled to APs)
– Asynchronous release
(delayed)
– Spontaneous/Tonic

From Hamilton & Attwell, 2010

 Non-exocytotic Release (glia)

 Non-Exocytotic
• xCT antiporter (glia)
– P2X
– VRAC
– EAAT
– Hemichannels

From Hamilton & Attwell, 2010

 Targets (Receptors)

 Ionotropic (iGluRs)
– NMDA (GluN1; GluN2a-d; GluN3a-b)
– AMPA (GluA1-4)
– KA (GluK1-5)

 Metabotropic (mGluRs)
– Group I (mGlu1 & mGlu5)
– Group II (mGlu2 & mGlu3)
– Group III (mGlu4, mGlu6-8)
Targets (Receptors)
Currents
Ionotropic Receptor Ligands
 Ionotropic Receptor Ligands
iGluR Agonists Antagonists
NMDA NMDA AP5 & AP7
Tetrazolylglycine Memantine* ; MK-801*
PP (GluN2A/B )
PEAQX (GluN2A)
PPDA (GluN2C/D
Ro 25-6981 (GluN2B)
Ifenprodil
AMPA AMPA NBQX, CNQX, DNQX
Quisqualate LY293558
Kainate ATPO
LY404187+ GYKI53655-
5-fluorowillardiine
Kainate Kainate LY382884
ATPA UBP302
iodowillardiine NS 3763-
LY339434
SYM 2081
+
Positive allosteric modulator
-
Negative allosteric modulator
* Channel blockers
From Watkins & Jane, 2009
 Ionotropic Receptors

From Pinheiro & Mulle, 2008

iGluR Distribution by in situ hybridization

From Porter et al., 1997

 iGluR Distribution by autoradiography

From Gao et al., 2000

 iGluR Distribution by transgenic c. elegans

From Brockie & Maricq., 2006

 Metabotropic Receptor Ligands

Group mGluR Agonists Antagonists Intracellular pathway

I mGlu1 DHPG ; ACPD LY367385 (mGlu1) ↑ PLC
mGlu5 CHPG (mGlu5) MCPG ↑ cAMP
Quisqualate MPEP (mGlu5)
-
↑ PKA
Ro 01-6128+ MTEP (mGlu5)
-

(mGlu1) CPCCOEt- (mGlu1)

DFB+ (mGlu5) BAY36-7620- (mGlu1)

II mGlu2 L-CCG-I LY341495 ↓ cAMP

mGlu3 LY354740 EGLU
LY487379+
III mGlu4 L-AP4 CPPG ↓ cAMP or cGMP
mGlu6 DCPG (mGlu8) UBP1112
mGlu7 PHCC+ (mGlu4)
mGlu8

+
Positive allosteric modulator
-
Negative allosteric modulator
From Watkins & Jane, 2009
 Metabotropic Receptors

From Loane et al., 2012

mGluRs Distribution by immunocytochemistry

GROUP I GROUP II GROUP III

From Ferraguti & Shigemoto, 2006

Synaptic Effects/ Transduction Systems

 Synaptic plasticity
 Short-Term: STP-STD
 Long-Term: LTP/LTD
• NMDA → >AMPA
• G-protein cascades (C-fos)
• Behavior (i.e. fear conditioning)
 Techniques: STED, uPAINT, STORM, etc
 Synaptic Effects: LTP/LTD
From Kakegawa & Yuzaki, 2005
 Transduction pathways: G-protein cascade

From Klann & Dever, 2004

 Behavior: Fear Conditioning

From Dantzer et al., 2008

Inactivation by uptake
 Recycling: Glutamate-Glutamine

P

From Nedergaard et al., 2002

‫شكرـا‬