Glutamate and GABA Flashcards
Describe the basic functions of Glutamate.
Widespread excitatory neuron in the brain.
Projection neurons that use glutamate: pyramidal in cortex, hippocampus, amygdala, thalamus and subcortical nuclei.
Classis neurotransmitters modify glutamate’s effect on neural activity.
Glutamate is ionized glutamic acid.
Glutamate is a major component of many proteins and has other metabolic roles
How is glutamate synthesized? What are the different transporters and distribution?
From glutamine by glutaminase.
Transporters
VGLUT 1, 2,3
- only found in glutamatergic neurons and are good markers.
-if these are knocked out it can be fatal.
Distribution: sometimes with other monoamines, which means that it can be stored and released as a cotransmitter (both released during firing) in many systems.
Shown by antibodies, mRNA distribution.
How can you tell if a cell uses glutamate as a neurotransmitter?
VGLUT transporters.
Label the transporter cause the enzyme glutaminase is not selective.
How is glutamate released and reuptaken?
Removed by Excitatory Amino Acid Transporters (EAAT 1-5)
EAAT 1-2 Astrocytes (glia-neuronmetabolic partnership)
EAAT 3: Presynaptic terminal
Astrocyes convert glutamate to glutamine (inert) by glutamine synthetase. (protects brain from excessive exitation)
Then back into neurons as glutamine for vesicular packaging as glutamate.
What happens if you knockout one EAAT transporter?
Animals are seizure prone, or there can be mutations in the gene that encode for transporters that cause ALS
Describe the different types of Ionotropic Glutamate receptors.
Named for their agonists.
AMPA
Kainate
NMDA
Ionotropic receptors of 4 subunits.
AMPA: glurR1-4 proteins
NMDA: nr1nr2 A-D (vary slightly)
Within each class there are differences in pharmacology function etc.
Describe the non-nmda recpetors. And some antagonists!
AMPA/Kainate allows Na+ into neuron to depolarize.
Always activated with enough glutamate
Activity tightly regulated and receptor will desensitize to too might stimulation
Kynurenic acid: nonselective antagonist that blocks non NMDA and NMDA receptors
NBQX: competitive antagonist that only blocks non-nmda receptors.
- causes sedation, reduced motor activity, ataxia, protects against seizures.
What is Kyneuric acid and NBQX?
- Antagonist: kyneuric acid, targtes all types of ionotropic glutamate recpetors
- NBQX: blcoks ampa and kanate (not NMDA) (more selective)
When you treat with NBQX you get a sedation, reduced motor activity, ataxia, protective against seizures.
Describe NMDA receptors in detail?
Na+ & Ca+ into cell
Causes more depolarization
1. Needs Glutamate and
2. Needs glycine or D-serince (co-agonists) to bind at the same time (there is a lot of glycine in CSF)
3. Needs Mg2+ to be unbound from the channel with depolarization from AMPA receptors (in close proximity)
What are some targets of NMDA receptors?
Competitive antagonists: block glutamate binding
- AP5 (APV)
Non-competitive antagonists: block receptor pore channel
- Phencyclidine (PCP)
- Ketamine
- MK-801 (dizocilpine)
- low doses cause schizophrenia like symptoms
- high doses cause ataxia and anesthesia
Glycine binding site: acts as a non-competitive antagonist, or an agonist.
- Agonists could help things like schizophrenia
What are the biophysical properties of AMPA and NMDA receptors? (excitatory effects)
ampa only: can get activated, but doesn’t have long lasting effect or depolarize it as much.
Nmda only: longer lasting effect, greater depolarization (cause they allow sodium and calcium to come in) - (need to remove all the magnesium to isolate this)
- NMDA can alter firing patterns (make burst firing happen)
BOTH CAN DEPOLARIZE CELLS BUT THEY DO IT IN DIFFERENT WAYS.
Describe metabotropic glutamate receptors.
mGLUR1-8
1 and 5: postsynaptic
2,3,4,6,7,8: presynaptic (autoreceptors to suppress glutamatre release)
LAP4: mGLUR 4678 agonist (suppress glutamate release)
- given to rats in the nucleus accumbens in a study*
Widely distributed, many functions, and might treat neuropsychiatric disorders in the future. (like schizophrenia where they have issues with glutamate transmission)
- target these receptors to normalize transmission
Describe synaptic plasticity.
Altering synapses, physical changes in the brain in response to learning and memory.
Measured by changes in PSPs for a certain input.
More strenght, larger EPSP
Measured by electrophysiology.
When this is done to a lot of neurons you can see it turns on groups of neurons the same way it was activated during the encoding.
Describe LTP
Long term potentiation
- Between communications of neurons. - Resembles what happens in real brain when its encoding a memory. - Alter synaptic strenth. - How LTP experiment work ○ Single neuron, patch clamp. Extitatory psps ○ mV depolarization when we stimulate. ○ Glutamate axons synapse at recorded neruon ○ Stimulate glutamate axons, so that they release glutamate on the neuron. ○ Records changes in membrane voltage. 1st: baseline measure. Gently stimluate every 15 seconds. Get some depolarization. (5mV strong, no AP, that's baseline) 2nd: do something, very high frequency (100x second), fires a lot of action potentials. (what happens when you experience something new as a new memory) 3rd: go back a minute later, stimulate slowly, they make a larger EPSP (more depolarization) - The previous intense activation, the synaptic strength was increased. Now more likey when activated to fire. - LTP can last weeks months years
When scaled up, or happens simultaneously, you have a NETWORK that might fire in similar patterns together.
What are the cellular mechanisms of LTP?
When NMDA receptors are activated a lot (in response to AMPA receptors being activated), they allow calcium into the cell.
Calcium activates kinases (CAM: callcium calmodulin) which
1. inserts new AMPA receptors into the membrane
2. Activates Protein kinase C Tyrosein Kinase (PKC TK) which leads to RETROGRADE MESSENGER such as nitric oxide (NO) to make more NT release!
This increase synaptic strength of pre and post synaptic mechanisms.
Mechanisms vary, only occur at a localized level and over time other changes can occur (change in shape or connectivity)
