Ch 8: Glutamate & GABA

Glutamate

Neuron that is an ionized form of glutamic acid

Glutamate Synthesis

Glutamine —Glutaminase—> Glutamate

Vesicular Glutamate Transporters (VGLUTs)

Moves glutamate into synaptic vesicles

VGLUT1

In cortex and hippocampus

VGLUT1 Knockout Mice

Survive birth but dies after week 3

VGLUT2

In subcortical areas

VGLUT3 Knockout Mice

Survive but are death

EAAT1

Highly found in astrocytes in cerebellum

EAAT3

Major neuronal glutamate transporter, postsynaptic localization

EAAT4

Mostly found in Purkinje cells in cerebellum

EAAT5

In bipolar cells in retina

EAAT2 Knockout Mice

Had seizures and short life span due to too much excitatory activity

Glutamine Synthetase

Astrocytes recycle glutamate by converting to glutamine

AMPA Receptors

For synthetic selective agonist AMPA, fast/excitatory glutamate responses mediated by stimulation of these

Kainate Receptors

For selective agonist kainic acid

NMDA Receptors

For synthetic agonist NMDA, lets both Ca2+ and Na+ pass

NBQX

Antagonist, blocks AMPA and kainate receptors

Effects of NBQX

Sedation, ataxia, decreased locomotor activity, seizure protection

D-serine

Must be synthesized enzymatically, d configuration, only in neurons

Coincidence Detection

Channel only opens when two events happen at the same time (binding of glutamate and co-agonist)

GABA

Major inhibitory AA transmitter, critical in regulating brain excitability

GABA Synthesis Pathway

Glutamate -GAD→ GABA

VGAT

Moves GABA and glycine to vesicles

GAT-1 and GAT-2

In neurons and astrocytes, remove GABA from synaptic cleft

GAT-3

Only in astrocytes, remove GABA from synaptic cleft

Tigabine

Selective GAT-1 inhibitor, increases extracellular GABA, enhances GABAergic transmission, treats epilepsy

GABA-T

Metabolizes GABA to glutamate & succinate

Vigabatrin

Irreversible GABA-T inhibitor, used for infantile spasms

Cortex and Hippocampus

Has interneurons

Striatum and Cerebellar Purkinje Cells

Has projections

Spinocerebellar Ataxias

Rare genetic mutation leading to degeneration and death of Purkinje cells

GABAA

Ionotropic

GABAB

Metabotropic

GABAA Receptor Subunits

2 α, 2 β, 1 γ

Muscimol

GABAA agonist from mushroom amanita muscaria

Bicuculline

Competitive antagonist for GABAA receptors, blocks GABA binding

Picrotoxin

Noncompetative antagonist, inhibits GABA function

BDZ, barbiturates, ethanol

Enhances GABA action

Diazepam

Increases GABA effect but alone has no effect, positive allosteric modulator, not agonist

Anesthetics

Enhances GABAA as allosteric modulators

Neurosteroids

Synthesized in brain by neurons and glia, acts as signaling molecules, targets allosteric binding sites on GABAA

GABAA Positive Allosteric Modulators

ALLO, THDOC, AS

GABAA Negative Allosteric Modulators

PS & DHEAS

Type I Catamenial Epilepsy

Estrogen/progesterone increases during ovulation

Type II Catamenial Epilepsy

Withdrawal from decreased progesterone during PMS

Status Epilepticus

Continuous epileptic seizures/very short time between, drugs targeting BDZ insensitive extra synaptic GABAA can help

Baclofen

GABAB agonist used as muscle relaxant