GABA/Glutamate

Glutamate is a ___ amino acid

nonessential: the body can make it, dont need to eat to get it

What are the main roles of glutamate in the body?

Building proteins and general metabolism.

Are all neurons glutamatergic?

No, all neurons contain glutamate, but only some package it into vesicles for neurotransmission.

What enzyme converts glutamine to glutamate?

glutaminase

What is VGlut? and what does it do?

Vesicular glutamate transporter; it moves glutamate from the cytosol (main fluid inside cell) into vesicles for release.

How many “flavors” of VGlut exist?

Three: VGlut1, VGlut2, VGlut3.

Which VGlut is common in the cortex and hippocampus?

VGlut1

Where is VGlut3 mostly found?

In cochlear hair cells.

Where is VGlut2 mostly found

in subcortical areas

What clears glutamate from the synapse after release?

Excitatory Amino Acid Transporters (EAATs)

How many types of EAATs are there? And which one is responsible for most of the reuptake? and where are these particular ones found

Five (EAAT1–EAAT5); mainly EAAT2 on astrocytes

What happens to glutamine after astrocytes make it?

It’s sent back to neurons for reuse or breakdown.

What enzyme converts glutamate into glutamine in astrocytes?

Glutamine synthetase.

Where is glutamate found in the brain?

Everywhere; it’s involved in multiple pathways.

What brain functions is glutamate important for? What mental disorders could it be involved in?

Synaptic plasticity, learning and memory, and cell death // SUDs and SCPT

Name the three main ionotropic glutamate receptors.

AMPA, Kainate, NMDA.

Which ions flow through AMPA and Kainate receptors? And which flow through NMDA receptors?

Sodium (Na⁺) // Sodium (Na⁺) and Calcium (Ca²⁺).

What happens when glutamate binds to ionotropic receptors?

The neuron depolarizes, starting an electrical signal.

What makes NMDA receptors unique compared to other glutamate receptors?

They are ion channels and activate second messenger systems (via Ca²⁺).

Which molecules must bind to NMDA receptors to activate them?

Glutamate and D-serine (co-agonists).

What blocks the NMDA receptor at resting potential? and how is it removed

Magnesium (Mg²⁺) plug; When the neuron becomes depolarized, Mg²⁺ falls off.

What are uncompetitive antagonists? give examples

Drugs that bind inside the NMDA channel to block ion flow (e.g., ketamine, PCP)

How many subtypes of metabotropic glutamate receptors exist?

Eight (mGluR1–mGluR8).

Which group of metabotropic glutamate receptors are postsynaptic and excitatory?

Group 1 (mGluR1 & mGluR5).

What pathway do Group 1 mGluRs use?

Phosphoinositide second messengers.

What do Group 2 and Group 3 mGluRs do?

They inhibit cAMP production, often acting as presynaptic or autoreceptors.

Which group includes mGluR2 & 3? Which group includes mGluR4, 6, 7, 8?

Group 2 // Group 3

Name some brain functions glutamate is involved in.

Cognition, motor coordination, locomotion, pain perception, mood.

Which psychiatric and neurological disorders are being targeted with mGluR drugs?

Depression, anxiety, schizophrenia, epilepsy, substance use disorders, cognitive impairment.

Why are NMDA and AMPA receptors targeted by cognitive enhancers?

They are critical for synaptic plasticity and learning/memory.

How do AMPA receptor allosteric modulators help cognition?

They make AMPA receptors stay active longer by reducing deactivation and desensitization.

What does “neurons that fire together, wire together” mean?

Repeated communication between neurons strengthens their connection

What is LTP and which receptor mediates it?

Long-term potentiation: A long-lasting strengthening of the connection between two neurons, linked to learning and memory; mediated largely by NMDA receptors.

What is “coincidence detection”?

When NMDA receptors only activate if glutamate is released and the postsynaptic neuron is already depolarized.

How can LTP be produced experimentally?

By applying a tetanic stimulus (rapid stimulation) and measuring an increase in the EPSP (the excitatory postsynaptic potential)

Where is LTP mainly studied?

In the hippocampus, though it could happen elsewhere

What is excitotoxicity?

Neuron damage or death caused by overactivation of glutamate receptors.

What happens when too much glutamate is present?

Prolonged depolarization that leads to cell damage or death.

What are the two main types of cell death in excitotoxicity?

Necrosis (cell bursting and release of intracellular contents into extracellular fluid) and apoptosis (programmed cell death, which occurs normally in young animals, but can cause excessive loss of neurons)

Does MSG in food cause excitotoxicity?

No — dietary MSG does not raise brain glutamate enough to cause damage.

Which disorders are linked to excitotoxicity?

Alzheimer’s disease (AD), Parkinson’s disease (PD), and some psychiatric disorders.

What does VGAT stand for? What is another name for it?

Vesicular GABA transporter or VIAAT (vesicular inhibitory amino acid transporter).

What is the function of VGAT?

It packages GABA into vesicles for release at the synapse.

What other NT’s can GABA be co-released with?

glycine, acetylcholine, or dopamine in some neurons.

Do GABA and other neurotransmitters share vesicles?

It’s unclear; they might share vesicles or be in separate ones — research is ongoing.

What removes GABA from the synapse?

GABA transporters (GATs).

How many types of GABA transporters are there? and where can they be found:

Three — GAT1, GAT2 (found in neurons and astrocytes) and GAT3 (found only in astrocytes)

What enzyme breaks down GABA?

GABA aminotransferase (GABA-T).

What does GABA-T produce from GABA?

Glutamate, which can be recycled or used by glutamatergic neurons.

What is the final metabolic product of GABA breakdown?

succinate, part of the energy (Krebs) cycle.

Where in the brain is GABA found?

Throughout the brain — especially in the striatum, cortex, hippocampus, septum, and amygdala.

What percentage of neurons in the amygdala are GABAergic?

70%

How is GABA involved in Parkinson’s disease?

The loss of dopamine neurons affects GABAergic interneurons in the striatum, disrupting motor control.

Name the GABAergic neurons important for fine motor control and where are they located?

Purkinje cells in the cerebellum

Can GABA be co-released with other neurotransmitters? give example

Yes — for example, GABA and acetylcholine (ACh) can be co-released in the basal forebrain.

What type of receptor is GABA_A

Ionotropic — it’s an ion channel that opens when GABA binds.

What ion passes through GABA_A receptors? and what happens when it passes inside the neuron?

Chloride (Cl⁻); It hyperpolarizes, making the neuron less likely to fire.

Where are GABA_A receptors located?

Postsynaptically — main site of inhibition.

Presynaptically — mediates phasic inhibition (short, fast bursts).

Extrasynaptically — mediates tonic inhibition (steady background inhibition).

What is phasic inhibition?

A brief, fast form of inhibition that occurs when GABA is released into the synapse and quickly activates receptors.

What is tonic inhibition?

A continuous, long-lasting inhibition caused by GABA binding to extrasynaptic receptors that stay active longer.

What kinds of substances can bind to GABA_A receptors (besides GABA)?

Benzodiazepines, barbiturates, ethanol (alcohol), and neurosteroids — all modulate receptor activity.

Why are GABA_A receptors important drug targets?

Because enhancing their activity calms the nervous system and reduces excitability.

What kinds of drugs act on GABA_A receptors?

Sedatives, hypnotics, anti-anxiety meds, anticonvulsants, and anesthetics

What do benzodiazepines do at the GABA_A receptor? Give example of benzodiazepine

They are positive allosteric modulators — they make GABA’s effect stronger but don’t activate the receptor by themselves. Valium (diazepam)

How does ethanol (alcohol) affect GABA_A receptors?

It enhances their activity, increasing inhibitory signaling and producing sedative effects.

What happens with chronic use of GABA_A-enhancing drugs?

The brain adapts, leading to tolerance, dependence, and withdrawal when the drug is removed.

What is an endozepine? also called a…

An endogenous (natural) compound that acts like a benzodiazepine — e.g., a neurosteroid

What neurosteroid is derived from progesterone and enhances GABA_A activity?

Allopregnanolone (ALLO) — it’s anticonvulsant, anti-anxiety, and sedating.

Which neurosteroids act as negative allosteric modulators at GABA_A? and what is their effect?

Pregnanolone sulfate (PS) and DHEAS — they can increase anxiety or seizure risk but might enhance cognition

What is catamenial epilepsy? and what % of women with epilepsy have it?

Seizure risk that fluctuates with the menstrual cycle due to changing progesterone/estrogen levels. 40-60%

How do hormones affect seizure risk in catamenial epilepsy?

Estrogen = proconvulsant; Progesterone (via ALLO) = anticonvulsant.

What is Type I catamenial epilepsy?

The periovulatory type, when estrogen spikes around ovulation, increasing seizure risk.

What is Type II catamenial epilepsy?

The perimenstrual type, when progesterone and ALLO drop right before menstruation, increasing seizure risk.

Why are benzodiazepines less effective during Type II catamenial epilepsy?

Because GABA_A receptors become less sensitive when ALLO levels drop.

What causes postpartum depression (PPD) in relation to GABA?

After childbirth, progesterone and ALLO levels drop sharply, disrupting GABAergic inhibition.

How does allopregnanolone treatment help PPD?

It restores GABA_A function and improves mood faster than traditional antidepressants

What hormonal changes are linked to PPD? and what % of women get PPD?

A rapid drop in progesterone and allopregnanolone (ALLO) after childbirth // 17%

What other system may contribute to PPD?

Dysregulation of the hypothalamic-pituitary-adrenal (HPA) stress axis.

What type of receptor is GABA_B?

Metabotropic (G-protein coupled).

Where are GABA_B receptors located

Both presynaptically and postsynaptically.

What do presynaptic GABA_B receptors do?

Inhibit calcium channels → reduce neurotransmitter release.

What do postsynaptic GABA_B receptors do?

Open potassium channels → hyperpolarize the neuron → reduce firing

GABA_B receptors affect cAMP by turning down ___ ___ (an enzyme) activity, thus reducing cAMP inside thecell

adenylyl cyclase

What functions are GABA_B receptors involved in?

Learning and memory, anxiety, depression, response to abused drugs.

How can drugs that enhance GABA_B receptors affect addiction?

They reduce neuron activity and neurotransmitter release, which dampens the brain’s response to addictive drugs.