CH 8 Flashcards by Hanna Song

Because glutamate is found throughout the brain, it is more difficult to assign specific ______ roles to these NTs. Glutamate is the ____ of everything that the brain does. All ______ cells in the cerebral cortex use glutamate, as well as projection neurons of the _____, ____ and _____. Glutamate projection neurons are _____ in other subcortical nuclei

functional, workhorse, pyramidal, thalamus, amygdala, hippocampus, embedded

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To varying degrees, most other “classical” neurotransmitters ______ effects of glutamate on neural activity.

modulate

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the non-ionized form of glutamate

glutamic acid

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glutamate serves as a ____ and also a component of many _____ and has other metabolic roles

NT, proteins

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the enzyme that converts glutamine to glutamate

glutaminase

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A _____ substance containing ____ ____ was found to make cells fire, which led to the discovery of the use of glutamate as a NT by neurons

salty, glutamic acid

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vesicular transporters that move glutamate into synaptic vesicles; only found in glutamatergic neurons

VGLUT1, VGLUT2, VGLUT3

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____ neurons don’t use glutamate bu get many glutamate inputs from the cortex

striatal

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Some cells will release a _____ NT such as DA or 5-HT and also glutamate togther. Neurons with different types of NT release will make different ____ _____ to release them (__). Sometimes, an axon may have different terminals that looks like either a _____ synapse or a ___ glutamate synapse. Moreover, ____ is sometimes expressed with markers of other transmitters

primary, axon terminals, collaterals, monoamine, wired, VGLUT

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_____ of glutamate is usually fatal

knockout

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Rapidly removes glutamate from the synapse and is on astrocyte glia (90% of glutamate reuptake)

EAAT1-2

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removes glutamate from the synapse

EAAT1 - EAAT5

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removes glutamate from the synapse; is on postsynaptic membrane

EAAT3

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Because too much ____ can mess up the activity of neurons and is ____ to humans, there are many safety procedures to remove glutamate.

excitation, toxic

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Majority of glutamate uptake is done by _____ that then convert glutamate to _____ by _____ _____. Storage of excess glutamate as ____ may protect the brain from excessive _______. This is then transported out of astrocytes and back to _____ to be turned back into glutamate

astrocytes, glutamine, glutamine synthetase, glutamine, excitation, neurons

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The 3 glutamate receptors are _____, ____ and _____, and are all ______. They consist of ____ subunit proteins and an ion channel. They have different ____ of subunits, explaining the differences in their pharmacology

AMPA, kainate, NMDA, 3, combination

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activation of _____/____ receptors allows entry of _____, depolarizing the neuron. These receptors are _____ activated when there is sufficient stimulation by glutamate. The _____ to glutamate is tightly regulated, as too much stimulation causes receptor _______. They may not _____ to glu as well, or ____ as wide, or pull receptors out of the membrane

AMPA, Kainate, Na+, always, sensitivity, desensitization, bind, open

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A nonselective antagonist for AMPA, Kainate and NMDA receptors

kyunurenic acid

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a competitive antagonist that blocks both AMPA and kainate receptors but not NMDA

NBQX

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treatment with high doses of AMPA/kainate antagonists like NBQX exhibit ______, reduced _____ activity, _____ and protection against _______.

sedation, locomotor, ataxia, seizures

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NMDA receptors allow flow of both ___ and ____ into the neuron and tends to cause a greater _____ that AMPA / Kainate receptors. To open the channel, both glutamate and ____ or _______ (co-agonists) must bind at the same time. The co-agonist binding site is ____ under most conditions because there is a lot of glycine in the CSF. In addition, when the neuron is at ___ ___, ____ ions are bound to a site in the channel, which blocks it. Repeated ____ receptor activation can depolarize the neuron enough to remove this block and allow NMDA receptor activation. This occurs with ____ firing

Na+, Ca2+, depolarization, glycine D-serine, occupied, resting potential, Mg2+, AMPA, burst

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A competitive agonist for NMDA receptors that block glutamate from binding

AP-5 / APV

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Drugs that block the NMDA channel when its open; independently of glutamate binding

Phencyclidine (PCP), ketamine, MK-801

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Noncompetitive antagonists of the NMDA receptor can cause ____-like symptoms at lower doses such as _____ and _______. At higher doses, they can cause ____ and then anesthesia

SZ, hallucinations, delusions, ataxia

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Certain noncompetitive antagonists target the _______ site. ____ agonists may act like a positive _____ _____

glycine-binding, glycine allosteric modulator

Activation of AMPA/Kainate vs NMDA receptors can have different ____ effects on postsynaptic neurons. NMDA receptors can induce _____/_____ lasting depolarization vs AMPA/Kainate. This can be tested by stimulating _____ glutamate inputs and using ____ to isolate the respective effects of each receptor. NMDA receptor activity can also alter _____ _____(e.g. promote burst firing)

excitatory, larger/longer, presynaptic, antagonists, firing patterns

Glutamate has ____ metabotropic receptors named ______. ______ and ______ are mostly postsynaptic, while other are mostly _______, which act as ____ or heteroreceptors. These receptors ____ glutamate or other transmitter release.

8, mGluR 1-8, mGluR1, mGluR5, presynaptic, autoreceptors, suppress

an agonist for mGluR 4,6,7, and 8 autoreceptors, which suppress glutamate release

L-AP4

mGluRs are ____ distributed and participate in many functions such as ____, motor _____, ___ and mood and ____ perception. Many mGluR drugs are being developed for treatment of many _____ disorders

widely, locomotion, coordination, cognition, pain, neuropsychiatric

The most studied function of glutamate receptors are their involvement in ____ ___ and ____/_____, which is measured by the activation of the _____ cell in response to stimulation. Alterations in the activity of ___ are thought to underlie learning as measured by changes in _____ strength. An increased strength means a larger ______ evoked in the postsynaptic neuron. The primary way this is measured is with _______ methods

synaptic plasticity, memory/learning, postsynaptic, synapses, synaptic, EPSP, electrophysiological

steps of LTP

1. stimulate presynaptic axons at low frequency to get a subthreshold EPSP (no APs) and establish baseline, 2. stimulate axons at a very high frequency (ie. tetanus) and get lots of APs in the postsynaptic neuron, 3. stimulate axons at low frequency again, and get a much bigger EPSP than before, that is more likely to evoke an AP

LTP can last for _____ and when the memory is recollected, same groups of ____ neurons that were activated when first forming the memory are activated

years, activated

In the early phase of LTP, high frequency activation of postsynaptic neurons allow ____ receptors to be activated, and _____ entry into the neuron. This is the most essential step. Then kinases such as _____ are activated, which hits latent ____ receptors floating inside the cell and inserts it into the ______. Other kinases such as ______ _____ ____ and _______ ____ can induce formation of a _____ ______ such as ______. ____ _____ undergo structural changes that make them more excitable (thicker, bigger), resulting in more _____ channels.

NMDA, Ca2+, calcium-calmodulin (CaM), AMPA, membrane, protein kinase C, tyrosine kinase, retrograde messenger, NO, dendritic spines, Na+

In early stage LTP, there is an increase in synaptic strength by both presynaptic (more _____ release) and postsynaptic (more _____) mechanisms

NT, receptors

In late stage LTP, the cell synthesizes new ______ that make these changes _____ _____

proteins, longer lasting

Injections of ____, ____ or ___ can lesion any brain nucleus. In _____ neurons, activating NMDA and non-NMDA receptors with high glutamate _____ most within a few hours

glutamate, kainate, NMDA, cultured, kills

prolonged depolarization of neurons which leads to eventual damage or death

excitotoxicity

fast death characterized by lysis due to osmotic swelling (blebs --> holes in membrane --> cellular disintegration)

necrosis

a slower death triggered by a series of biochemical events; lysis does not occur

apoptosis/programmed necrosis

Apoptosis / programmed necrosis results in death in _____ hours. It can be induced by lower ______ and longer exposure time to glutamate, and depends on ____ receptor activation. The excess ____ causes ____ enzymes to be activated which stripes down the cells and kills them

18-24, concentration, NMDA, Ca2+, killer

interruption of blood flow from stroke or heart attack; excitotoxic brain damage may occur

brain ischemia

Excitotoxic brain damage may occur with brain ischemia because a lack of _____ means the Na+/K+ _______ stops working, and neurons depolarize, resulting in a massive glutamate release in the affected area. Eventually, the high ____ levels overloads ____ and they cannot compensate, resulting in _____ enzyme activation. NMDA _____ may not work because once the process has already started, the _____ are already activated even if the ____ is stopped. This results in a degradation of _____ within the dying cells. However, treatment may be effective if we can deactivate the enzymes before ____ ___ occurs

O2, pump, Ca2+ buffers, killer, antagonists, enzymes, excitation, function, cell death

when a stroke occurs, a ____ ____ stops the flow of blood to a brain region. Drugs that ___ them may restore flow to avoid further damage. Without ___ and ___, neurons begin to depolarize and produces APs. Drugs that inhibit the ____ ____ ____ may reduce the number of APs generated. Many of these neurons release _______. In addition, the lack of energy in the ____ neuron causes the glutamate ______ to stop working. Drugs that block _____ ____ may combat the excessive stimulation. Postsynaptic neurons also produce action potentials, so excess amounts of ____ and ____ enter the cell. This causes ____ ____. Drugs that block _____ _____ may avert the intracellular buildup of Ca2+

blood clot, dissolve, oxygen, glucose, voltage-gated Na+ channels, glutamate, presynaptic, transporters, glutamate receptors, Ca2+ Zn2+, cell death, Ca2+ channels

the primariy inhibitory transmitter in the brain

GABA (gamma-aminobutyric acid)

Secondary inhibitory transmitter found mostly in the back of the brain

glycine

all ___ ______ neurons in the striatum and other nuclei with the ____ ____ use GABA. ____ neurons intermixed within monoamine cell groups also use GABA. ______ in the cerebral cortex (_____% of all neurons) such as in the ____, ___ and other brain regions also use GABA.

medium spiny, basal ganglia, projection, interneurons, 30, hippocampus, amygdala

GABA acts like a ____ for information coming into neurons. It regulates different _____ of firing in the ______ (e.g. burst firing). One GABA neuron can make connections with up to _____ other neurons in the cortex

filter, patterns, cortex, 80

Reduced GABA activity promotes ______. Many brain circuits are set up as a series of inhibitory ______ connections, and works through a processes of _______.

seizures, GABAergic, disinhibition

_____ cells can fire without excitation and fires at _____Hz on _____ ____ cells. These cells fire at ____Hz back to pallidum cells which lower in firing and _____ the ventral striatum to produce _____

pallidum, 70, ventral striatum, 0-3, disinhibit, movement

the enzyme that converts glutamate to GABA; only in GABA cells

glutamate decarboxylase (GAD)

the transporter that moves GABA into vesicles

vesicular GABA transporter

There are examples where GABA is contained in the same ____ and possibly even the same ____ as other NTs. The effect depends on the number of _____ receptors

terminals, vesicles, postsynaptic

GABA reuptake transporters

GAT1 - GAT3

GAT-1 is located on ________ _______, whereas all 3 transporters are on _____ that mop.up GABA in a similar manner to _____

presynaptic terminals, astrocytes, glutamate

the enzyme that converts glutamate to glutamine in astrocytes

glutamine synthase

glutamine can be released by astrocytes, taken up by ______ and converted back to ______ and used to remake ______. Some therapeutic drugs target ____ to elevate GABA levels; this is used for _____ treatment which causes more _____ to offset the excitation

neurons, glutamate, GABA, GAT, epilepsy, inhibition

GABA-A is _____, allowing ___ to move from the outside to the inside of the cell, causing ______. This subtype has multiple ____ where drugs and other molecules can bind to affect its function. Each receptor consists of ____ subunits of various combinations of _____, _____, _____ and _______ types. Most have ___ of each and 1 _____. This makes the receptor more or less _____ to GABA depending on the subtypes

ionotropic, Cl-, hyperpolarization, sites, 5, alpha, beta, gamma, delta, 2, gamma, sensitive

GABA-A competitive agonist (at GABA binding site)

muscimol

GABA-A competitive antagonist

bicuculline

GABA-A non competitive antagonist that binds inside the channel pore

picrotoxin

where the endogenous ligand binds

orthosteric binding site

_____ and ______ bind to receptors at sites distinct from the GABA binding site. These drugs increase ____ of GABA to open the receptor channel but do not open the channel is GABA is also not bound (ie. act as _____ _____ _____). Benzodiazepines only bind to receptors containing the _____ subunit (most receptors have them). _____ acts in a similar manner at the BDZ site, causing more ____ when mixed with them

benzodiazepines, barbiturates, potency, positive allosteric modulators, gamma, alcohol, inhibition

a benzodiazepine that is used for sleep but reduces sleep quality because REM sleep is reduced over the sleep cycle

diazepam (valium)

barbiturate

phenobarbital

some drugs at like the BDZ, but bind to different parts of the receptor, not just the beta subunit

neurosteroids binding site

Some drugs can act as ____ agonists at the BDZ site. They do not have an effect on their own, but _____ ability of GABA to open the channel, by stabilizing an _____ form of the channel. This promotes ____, ____ and _____.

inverse, attenuates, inactive, anxiety, arousal, seizures,

GABA-B receptors are _____ and require ____ different subunits to assemble in the membrane and work properly. Activation of these receptors has an _____ effect on postsynaptic cells by _____ channel opening and inhibiting _____ formation. They also reside _____ where they serve as ______ or heteroreceptors.

metabotropic, 2, inhibitory, K+, cAMP, presynaptically, autoreceptors

a GABA-B reveptor agonist used as a muscle relaxant and experimental treatment for alcoholism

baclofen

a GABA-B receptor antagonist that is a convulsant and is primarily used for research

saclofen

Blockade of ____ receptors impairs many forms of learning mediated by ______, ____ and _____. This is shown in rats given a _____ _____ ______ which severely impairs learning to find the platform quickly in the _____ _____ ______.

NMDA, hippocampus, amygdala, striatum, NMDA receptor antagonist, morris water maze

NMDA antagonists that impair learning also impair the formation of _______. If you block the NMDA receptors during the high ___ activation of the ____ pathway, no ____ occurs. Enhancing glutamate activity can ____ learning/memory

LTP, frequency, glutamate, improve

positive allosteric modulators of AMPA receptors

ampakines

ampakines do not _____ AMPA receptors, but prolong _____ ____ and reduce _______. Ampakines can improve ____ in animals performing the _____ ____ ____ _____ task

activate, open time, desensitization, cognition, delayed match to sample

ampakines do not _____ AMPA receptors, but prolong _____ ____ and reduce _______. Ampakines can improve ____ in animals performing the _____ ____ ____ _____ task

activate, open time, desensitization, cognition, delayed match to sample

A task in which an animal is trained to move a cursor to the center of a shape, experience a 1-30s delay, then must select the shape that the animal first saw out of 3 other stimuli

delayed match to sample task

GABA is metabolized to _____ and ____ by _____ ______. In astrocytes, then glutamate is converted to _____

glutamate, succinate, GABA aminotransferase (GABA-T), glutamine

The enzyme that metabolizes GABA to Glutamate and succinate

GABA aminotransferase (GABA-T)