NEU 490 Exam 3

Question 1

Biogenic Amines which 5?

Biogenic amine transmitters regulate many ????

Implicated in a wide variety of behaviors, and defects in their function is implicated in??

Catecholamines: which 3?
– Named because they share a common ???
– Tyrosine via tyrosine hydrolyze to ????

Catecholamine Receptors
– All Catecholamine receptors are ???
– Dopamine: ???
– Epinephrine and Norepinephrine: ???
— These can all be ???
– Inactivation is done via uptake, followed by metabolism - ????

Answer 1

Biogenic Amines Dopamine, Norepinephrine, Epinephrine, Serotonin, Histamine - regulate variety of brain and peripheral functions and deficiency are implicated in most psychotic disorders

Biogenic amine transmitters regulate many brain functions and are also active in the peripheral nervous system

Implicated in a wide variety of behaviors, and defects in their function is implicated in many psychiatric disorders

Catecholamines: Dopamine, Norepinephrine, Epinephrine
– Named because they share a common precursor, the amino acid tyrosine
– Tyrosine via tyrosine hydrolyze to dopa

Catecholamine Receptors
– All Catecholamine receptors are metabotropic
– Dopamine: D1-4 subtypes
– Epinephrine and Norepinephrine: Alpha 1-2, Beta 1-4 subtypes
— These can all be inhibitory OR excitatory
– Inactivation is done via uptake, followed by metabolism - in transporter to presynaptic cell and via specific enzymes in the synaptic cleft

Question 2

Dopamine: Catecholamine

Expressed in the CNS and PNS - major area in brain is??

Highly expressed throughout ???

Dopamine plays an important role in:
1. Motor coordination (WHICH AREA); Dysfunction of these areas: ???
2. Motivation, reward, and reinforcement (WHICH AREA); Dysfunction of these areas: ????

VTA to PFC and other cortical areas → mesocortical pathway, nigrostriatal pathway(substantia nigra to out striatum, ubero infundibular pathway, mesolimbic pathway

Reuptake Catabolism - taken up ??

D2 = presynaptic inhibition - ???

Dopamine packaged into vesicles via ???

Reversible binding of ???

Dopamine Receptors:
1. Once released, dopamine acts exclusively by activating??
2. The monomeric structure of this receptor closely parallels that of other ???
3. D1-like receptors (D1 and D5) are ???
4. D2-like receptors (D2, D3, and D4) are ??
5. Gs Excites - ???
6. Gi inhibit ???
7. Antagonist: ???
8. Agonist: ???
9. Dopamine circuit function depends on ???

NET = ??

DAT = ??

VMAT2 = ??

TH = ??

AAD = ??

COMT = ???

MAO = ??

AD = ??

HVA = ??

OCT = ??

Answer 2

Dopamine: Catecholamine

Expressed in the CNS and PNS - major area in brain is corpus striatum

Highly expressed throughout multiple pathways in the brain

Dopamine plays an important role in:
1. Motor coordination (substantia nigra); Dysfunction of these areas: Parkinson’s
2. Motivation, reward, and reinforcement (ventral tegmental area); Dysfunction of these areas: Addiction - many drugs of abuse work here

VTA to PFC and other cortical areas → mesocortical pathway, nigrostriatal pathway(substantia nigra to out striatum, ubero infundibular pathway, mesolimbic pathway

Reuptake Catabolism - taken up via DAT dopamine transporter

D2 = presynaptic inhibition - presynaptic release DA that then acts on itself to inhibit more release and negative feedback

Dopamine packaged into vesicles via vesicular monoamine iransports (VMAT)

Reversible binding of D1, D2 family of receptors - all GPCR (Gs or Gi)

Dopamine Receptors:
1. Once released, dopamine acts exclusively by activating G-protein-coupled receptors
2. The monomeric structure of this receptor closely parallels that of other metabotropic receptors
3. D1-like receptors (D1 and D5) are Gs GPCRs excitatory
4. D2-like receptors (D2, D3, and D4) are Gi GPCRs inhibitory
5. Gs Excites - stimulate adenylyl cyclase activity to increase cAMP – D1
6. Gi inhibit Ac and crease cAMP - D2
7. Antagonist: Schizophrenia D2, Addiction D3
8. Agonist: Parkinson’s Restless Leg D1, Parkinson’s D2, ADHD D4
9. Dopamine circuit function depends on subtype of DR expressed on that circuit

NET = norepinephrine transporter

DAT = dopamine transporter

VMAT2 = Vesicular monoamine transporter

TH = Tyrosine Hydroxylase

AAD = aromatic amino acid decarboxylase

COMT = Catecholamine O-methyl-transferase

MAO = monoamine oxidase

AD = aldehyde dehydrogenase

HVA = Homovallinic Acid

OCT = organic cation transporter

Question 3

Dopamine: Catecholamine

Role in the Central Nervous System:
1. Nigrostriatal pathway: ???

2. Mesolimbic and Mesocortical pathway: ???

3.Tuberoinfundibular/tubero- hypophyseal pathway: ???

Role for DA in the Peripheral Nervous System:
1. Circulating and locally ??
3. Kidney, Gut and Heart:
– Vasodilation of r??
– Kidney diuresis and natriuresis ???
– Inhibits motility in??
– Stimulates motility in ??
– Activates β1 receptors (not a dopamine receptor) in the heart ???
3. Neuron-dependent and ???

Answer 3

Dopamine: Catecholamine

Role in the Central Nervous System:
1. Nigrostriatal pathway: Substantia nigra to striatum - control of voluntary movement (dysfunction of parkisson)

2. Mesolimbic and Mesocortical pathway: Ventral Tegmental Area (VTA) to Mesocortical/Mesolimbic areas - reward, mood, drug addiction, schizophrenia

3.Tuberoinfundibular/tubero- hypophyseal pathway: VTA to Hypothalamus – released from and tonically inhibits pituitary prolactin secretion - important role in lactation

Role for DA in the Peripheral Nervous System:
1. Circulating and locally formed dopamine
3. Kidney, Gut and Heart:
– Vasodilation of renal vascular beds (D1)
– Kidney diuresis and natriuresis (D1, D2) - diuresis increase water excretion and natriuresis increase Na excretion — expressed in sympathetic nerves
– Inhibits motility in the upper gut (D1)
– Stimulates motility in the colon (D2)
– Activates β1 receptors (not a dopamine receptor) in the heart, increasing heart rate and contractility
3. Neuron-dependent and independent sources of DA

Question 4

Question:

Glycine receptors are fill in blank (ionotropic, metabotropic, or both) and fill in blank (inhibitory, excitatory, or both).

Dopamine receptors are fill in blank (ionotropic, metabotropic, or both) and fill in blank (inhibitory, excitatory, or both).

Death of dopaminergic neurons leads to _______________, whereas dysfunction of the mesolimbic pathway can lead to ______________.

Answer 4

ionotropic, inhibitory

metabotropic, both

Answer: Parkinsons; Addiction

Question 5

Norepinephrine/ Epinephrine: Catecholamine

Norepinephrine:
1. Norepinephrine is used as a NT in the ???????; Influences????
2. The most prominent noradrenergic neurons are ??? This is the major peripheral transmitter in this division of the ????
3. Catalysing dopamine into ???

Norepinephrine localization:
1. Distribution of neurotransmitter systems in ???
2. Functions:
– Widespread projections from locus ???
– Activation????
– Peripheral NS is pregang of parasympathetic and sympathetic release Ach onto gang neurons or adrenal medulla. Post gang in sympathetic axons and adrenal medulla release norepinephrine - ???

Answer 5

Norepinephrine/ Epinephrine: Catecholamine

Norepinephrine:
1. Norepinephrine is used as a NT in the locus coeruleus, a brainstem nucleus that projects diffusely to a variety of forebrain targets; long range projections from locus coeruleus to widespread parts of the brain a lot of cortical areas;; Influences sleep and wakefulness, arousal, attention, and feeding behavior
2. The most prominent noradrenergic neurons are sympathetic ganglion cells. This is the major peripheral transmitter in this division of the visceral motor system; sympathetic nervous system(emergency fight or flight)
3. Catalysing dopamine into norepinephrine

Norepinephrine localization:
1. Distribution of neurotransmitter systems in the human brain
2. Functions:
– Widespread projections from locus coeruleus - really long axons through whole brain
– Activation (attention, wakefulness) CNS
– Peripheral NS is pregang of parasympathetic and sympathetic release Ach onto gang neurons or adrenal medulla. Post gang in sympathetic axons and adrenal medulla release norepinephrine - cell bodies gang located in the sympathetic chain and adrenal medulla sits on top of kidneys release norepinephrine right into blood stream – can be excitatory or inhibitory

Question 6

Norepinephrine/ Epinephrine: Catecholamine

Norepinephrine Receptors in the PNS:
1. Receptors for Norepinephrine called ???
2. Two major classes: alpha and beta
3. Alpha (α) (subtypes α1, α2):
– A1 – ???
– A2 – ???
4. Beta (β) (subtypes β1, β2 , β3) - meds can target these blockers for ???
– B1 – ???
– B2 – ????
– B3 – ???
5. Effects of NE depend on which subclass of receptor predominates on ???
– Alpha 1 and Beta 1 – stim or inhbit??
– Alpha 2, Beta, 2, Beta 3 - stim or inhbit ???

Norepinephrine Receptors in the CNS:
1. Neuromodulator in the CNS so more ???
2. Acts on β-adrenergic receptors on ?????
3. Facilitates Glutamate and K+ ?????
4. Stimulates ????

Sympathetic Pathway: fight or flight
1. EPI produced primarily by the ??????
2. Epipen can bind to ?????

Answer 6

Norepinephrine/ Epinephrine: Catecholamine

Norepinephrine Receptors in the PNS:
1. Receptors for Norepinephrine called Adrenergic Receptors - GPCR
2. Two major classes: alpha and beta
3. Alpha (α) (subtypes α1, α2):
– A1 – Blood vessels of skin, mucus membranes, abdominal organs (CONSTRICTS)
– A2 – adrenergic axon terminals (inhibit release of NE)
4. Beta (β) (subtypes β1, β2 , β3) - meds can target these blockers for HBP so target to decrease BP and HR
– B1 – HEART, (Increase CO)
– B2 – Bronchioles and visceral smooth muscle
– B3 – Fat tissue
5. Effects of NE depend on which subclass of receptor predominates on target organ
– Alpha 1 and Beta 1 – stimulatory
– Alpha 2, Beta, 2, Beta 3 - inhibitory

Norepinephrine Receptors in the CNS:
1. Neuromodulator in the CNS so more sculpts
2. Acts on β-adrenergic receptors on neuronal pyramidal cells, with little effect on its own but instead, primes cell for more powerful response to excitatory input such as glutamate by increasing phosphorylation of K channels, decreasing their opening and increasing the excitability of cells - reminder pyramidal cells express glutamate and more K stays in cell
3. Facilitates Glutamate and K+ Uptake into Astrocytes
4. Stimulates Glucose Production from Glycogen

Sympathetic Pathway: fight or flight
1. EPI produced primarily by the chromaffin cells of the adrenal medulla (gland) and is secreted into the bloodstream
2. Epipen can bind to epinephrine to open blood

Question 7

Serotonin:

Serotonin (or 5-hydroxytryptamine/ 5-HT) is found primarily in groups of neurons in the ?????

These have widespread projections to the ???

A large number of drugs that are valuable in the treatment of ????????

Synthesis and Termination of Serotonin:
1. 5-HT is synthesized from the ?????
2. Tryptophan taken up into neurons via transporters - ??????
3. Loading of 5-HT into synaptic vesicles is done by ????
4. The synaptic effects of serotonin are terminated by:
– Transport back into nerve terminals via ??????
– Degraded by ?//???
5. Many antidepressant drugs are ????????
6. Older class of antidepressants are MOIS or monoamine oxidation inhibitors and ?????

Answer 7

Serotonin:

Serotonin (or 5-hydroxytryptamine/ 5-HT) is found primarily in groups of neurons in the raphe region of the pons and upper brainstem

These have widespread projections to the forebrain and cortical routes and regulate sleep and wakefulness.

A large number of drugs that are valuable in the treatment of depression and anxiety act on serotonergic pathways - SSRI selective serotonin reuptake inhibitors

Synthesis and Termination of Serotonin:
1. 5-HT is synthesized from the amino acid tryptophan, which is an essential dietary requirement.
2. Tryptophan taken up into neurons via transporters - rate limiting step tryptophan hydroxylase convert to 5-HT then loaded into synaptic vesicles by VMAT
3. Loading of 5-HT into synaptic vesicles is done by the VMAT
4. The synaptic effects of serotonin are terminated by:
– Transport back into nerve terminals via a specific serotonin transporter (SERT) that is present in the presynaptic plasma membrane, where they are then repackaged - this is the transport targeted by SSRIs
– Degraded by MAO (monoamine oxidase)
5. Many antidepressant drugs are selective serotonin reuptake inhibitors (SSRIs) that inhibit transport of 5-HT by SERT - target transporter
6. Older class of antidepressants are MOIS or monoamine oxidation inhibitors and target anything enzyme

Question 8

Serotonin Receptors:

A large number of 5-HT receptors have been identified. Most 5-HT receptors are ??????

Metabotropic Receptors - monomeric structure:
1. 5-HT4/6/7 – ????
2. 5-HT1/5 – ????
3. 5-HT2 – ????????
4. Implicated in a wide range of behaviors, including ???????
5. Impairments in the function of these receptors have been implicated in ?????

Ionotropic Receptor:
1. 5HT-3 is a ligand-gated ion channel that ????
2. 5HT3 Ionotropic ?????
3. Gating Na so K ?????

Why do you think that initial side effects of SSRIs are typically gastrointestinal in nature, whereas it takes 6-10 weeks for changes in depressive and/or anxiety symptoms to occur? What are other side effects you might anticipate, given the role of serotonin in the CNS?
– Maybe it takes ?????

Answer 8

Serotonin Receptors:

A large number of 5-HT receptors have been identified. Most 5-HT receptors are metabotropic, with one subtype that is ionotropic.

Metabotropic Receptors - monomeric structure:
1. 5-HT4/6/7 – Gs coupled: decrease K conductance so less K leaves slow depo
2. 5-HT1/5 – Gi coupled: increase K conductance so more K leaves hypo
3. 5-HT2 – Gq coupled: decrease K conductance so less K leaves slow depo
4. Implicated in a wide range of behaviors, including circadian rhythms, motor behaviors, emotional states, and state of mental arousal.
5. Impairments in the function of these receptors have been implicated in numerous psychiatric disorders

Ionotropic Receptor:
1. 5HT-3 is a ligand-gated ion channel that allows sodium and calcium to enter through the pore
2. 5HT3 Ionotropic excites
3. Gating Na so K fast depo so entrance of Na

Why do you think that initial side effects of SSRIs are typically gastrointestinal in nature, whereas it takes 6-10 weeks for changes in depressive and/or anxiety symptoms to occur? What are other side effects you might anticipate, given the role of serotonin in the CNS?
– Maybe it takes time for the brain to actually change its structures and plasticity to the new drugs. Then it is easier for the body to react to a change immediately compared to the brain so the gut will react faster.

Question 9

Histamine:

Histamine is found in neurons in the ??????

Central histamine and peripheral histamine play different functions:
1. Histamine released by neurons: ??????
2. Histamine released by mast cells: ???????
3. Histamine may play a role in brain ?????

Histamine is produced from the amino acid ????

Histamine degraded by combined actions ?????

VMAT - no plasma membrane histamine transport ???

Histamine Distribution:
1. Central Expression: ???????
2. Peripheral Expression: ?????
3. Mast cells aligned near ????

Answer 9

Histamine:

Histamine is found in neurons in the hypothalamus that send sparse but widespread projections to almost all regions of the brain and spinal cord

Central histamine and peripheral histamine play different functions:
1. Histamine released by neurons: arousal, attention, and reactivity of the vestibular system - vestibular is our system for balance and dysfunction cause dizzy/vertigo
2. Histamine released by mast cells: released upon tissue damage and allergic reactions - mast cells: innate immune system, located close by to blood vessels and release of histamine to cause vasodilation
3. Histamine may play a role in brain blood flow

Histamine is produced from the amino acid histidine, by histidine decarboxylase

Histamine degraded by combined actions histone methyltransferase and monoamine oxidase

VMAT - no plasma membrane histamine transport has been identified

Histamine Distribution:
1. Central Expression: Tuberomammillary nucleus of the hypothalamus
2. Peripheral Expression: Mast cells, skin, lungs, GI mucosa (storage granules) - histamine is packaged into granules - Mast cells release histamine
3. Mast cells aligned near blood vessels!

Question 10

Histamine Receptors - target antihistamine due to role in allergies and all are metabotropic:::::
1. Gq H1 Receptor: Increase ????????
2. Gs H2 Receptor: Increase ??????/
3. Gi H3 Receptor (presynaptic autoreceptors): Decrease ??????
– Located at axon terminal - autoreceptor that elicits ????

Presynaptic Autoreceptor:
1. Histamine H3 receptors are expressed in the ?????????, where they act as autoreceptors in presynaptic histaminergic neurons and control ???????????????
2. Axon terminal of presynaptic neuron and negative feedback ????????
3. Autoreceptor - Only sensitive to the ?????????
4. Heteroreceptor - Sensitive to NT not ????????
5. Transporters - Transport proteins that reuptake of NT ?????????

Answer 10

Histamine Receptors - target antihistamine due to role in allergies and all are metabotropic:::::
1. Gq H1 Receptor: Increase Ca leads to smooth muscle contraction, increase capillary permeability, vasodilation, and sensory nerve ending pain and itching - H1 receptor on nociceptors
2. Gs H2 Receptor: Increase cAMP leads to increase gastric acids secretion, blood vessels for vasodilation, increase capillary permeability
3. Gi H3 Receptor (presynaptic autoreceptors): Decrease cAMP leads to decrease histamine release, decrease secretion, and vasodilation
– Located at axon terminal - autoreceptor that elicits negative feedback and reduces histamine released from presynaptic neuron

Presynaptic Autoreceptor:
1. Histamine H3 receptors are expressed in the central nervous system and to a lesser extent the peripheral nervous system, where they act as autoreceptors in presynaptic histaminergic neurons and control histamine turnover by feedback inhibition of histamine synthesis and release, mainly CNS
2. Axon terminal of presynaptic neuron and negative feedback H3 → Gi
3. Autoreceptor - Only sensitive to the NT released by the neuron
4. Heteroreceptor - Sensitive to NT not released by the cell
5. Transporters - Transport proteins that reuptake of NT, there is no specific histamine transport that’s been found!

Question 11

Histamine Actions in CNS

Neuromodulator (alter effects of other NTs) and Itself act as a ????????/

Regulate and be regulated by other ??????

Participate in Variety of brain functions:
1. Increase ???
2. Enhance ????
3. Regulates ????
4. Modulates ????
5. Regulates ????
6. Induce ?????/

CNS Effects of AntiHistamines (inhibiting histamine) - common antihistamines are ?????

CNS depression - side effects: ?????

Answer 11

Histamine Actions in CNS

Neuromodulator(alter effects of other NTs) and Itself act as a Classical Neurotransmitter

Regulate and be regulated by other neurotransmitters

Participate in Variety of brain functions:
1. Increase wakefulness and is mediator of arousal
2. Enhance learning and retention of tasks
3. Regulates hypothalamic function (neuroendocrine responses)
4. Modulates food and water intake (satiety)
5. Regulates vascular changes
6. Induce vomiting (brainstem emetic centers-particularly in response to vestibular disturbances

CNS Effects of AntiHistamines(inhibiting histamine) - common antihistamines are Benadryl (itchy) and Dirmanamine (motion sick)

CNS depression - side effects: Sedation, Drowsiness, Anti-motion sickness, Anti-emetic, Anti-vertigo

Question 12

Purines: ATP and Adenosine
Purine Neuromodulator/NT - ATP + Adenosine

All synaptic vesicles contain ATP, which is co-released with ??????

It has been known since the 1920s that the extracellular application of ATP (or its breakdown products AMP and adenosine) can elicit ??????

The idea that some purines are also neurotransmitters is now well established. ATP acts as an excitatory neurotransmitter in ?????????

Also highly expressed in ????????

NT ATP and Adenosine: Adenosine not considered classic NT it’s not stored in ??????? ATP make???????
1. Adenosine has its own set of ????
2. Enzyme degrade ATP into Adenosine and can ?????
3. Effector cell membrane: ?????

Answer 12

All synaptic vesicles contain ATP, which is co-released with one or more “classic” neurotransmitters

It has been known since the 1920s that the extracellular application of ATP (or its breakdown products AMP and adenosine) can elicit electrical responses in neurons - receptors that ATP bound to on neurons

The idea that some purines are also neurotransmitters is now well established. ATP acts as an excitatory neurotransmitter in motor neurons of the spinal cord, as well as in sensory and autonomic ganglia.

Also highly expressed in microglia and astrocytes as well as their receptors - a lot of cross talk between neurons and glia using ATP

NT ATP and Adenosine: Adenosine not considered classic NT it’s not stored in synaptic vesicles or released in Ca dependent manner – so only had Adenosine if ATP is catalyzed to make Adenosine
1. Adenosine has its own set of actions
2. Enzyme degrade ATP into Adenosine and can excite like P2X and some P2Y or inhibit some P2Y
3. Effector cell membrane: postsynaptic neurons or peripheral end organ

Question 13

Purines: ATP and Adenosine
Purine Neuromodulator/NT - ATP + Adenosine

ATP Receptors; Three classes of purinergic receptors are known: which 3?

Ionotropic Receptor:
1. P2X receptors - ??
2. Mediate EPSPs - ???
3. Widely distributed in ???

Metabotropic Receptors:
1. ???? receptors
2. Preferentially activated by ?????
3. Xanthines such as caffeine ??????

P2Y receptors:
1. Preferentially activated by ????
2. Located on ????
3. Diff subtypes of 2Y:
– Gs: A2 - ???
– Gi/Go: A1/A3 - ????

Important Roles for ATP and Adenosine in Disease:

1. Synaptic Plasticity
   — Adenosine: presynaptic neuron modulation binding to adenosine receptor on ????
   — P2X Receptor ATP: fast synaptic ???/
2. Pain
   — P2X4: expression upregulation on ???
3. Ischemia - P2X + P2Y ????/
4. Neuroinflammation - P2X + P2Y ?????

Answer 13

ATP Receptors; Three classes of purinergic receptors are known: Ionotropic Receptor, Metabotropic Receptors, P2Y receptors

Ionotropic Receptor:
1. P2X receptors - excitatory
2. Mediate EPSPs - entrance of cation
3. Widely distributed in central and peripheral neurons, in addition to brain microglia

Metabotropic Receptors:
1. Adenosine receptors
2. Preferentially activated by adenosine
3. Xanthines such as caffeine block adenosine receptors

P2Y receptors:
1. Preferentially activated by ATP
2. Located on neurons, microglia, and astrocytes
3. Diff subtypes of 2Y:
– Gs: A2 - excite adenylyl cyclase
– Gi/Go: A1/A3 - inhibit adenylyl cyclase

Important Roles for ATP and Adenosine in Disease:

1. Synaptic Plasticity
   — Adenosine: presynaptic neuron modulation binding to adenosine receptor on presynaptic neurons alternating release of NT
   — P2X Receptor ATP: fast synaptic ionotropic transmission and synaptic plasticity
2. Pain
   — P2X4: expression upregulation on microglia after injury - ATP signaling through microglia for chronic pain
3. Ischemia - P2X + P2Y glial cross talk with neurons
4. Neuroinflammation - P2X + P2Y glial cross talk with neurons

Question 14

Question:

D1-like dopamine receptors are fill in blank (excitatory or inhibitory). Beta-2 norepinephrine receptors are fill in blank (excitatory or inhibitory). 5HT3 receptors are fill in blank (ionotropic or metabotropic).

Histamine is released by:

ATP is released by:

Answer 14

Answer: excite, inhibit, ionotropic

Histamine is released by: Answer: neurons and mast cells

ATP is released by: Answer: neurons, microglia, and astrocytes

Question 15

Synapse Structure: Importance of Dendritic Spines

Dendritic Spines:
1. 1 spine = ???
2. Can monitor spine number to look at ???
3. Morphological specializations that produce from dendrites
– ?? mm
– 1-10 ???
4. ??? synapses
5. PSD95: ???

Types of Dendritic Spines:
1. Dendritic spines are tiny ?????

2. ????? size and shape, and modifiable by a????? - presynaptic activity the more ???????
3. Dendritic spines have been classified by ??????? which type?????

Answer 15

Synapse Structure: Importance of Dendritic Spines

Dendritic Spines:
1. 1 spine = 1 synapse
2. Can monitor spine number to look at synaptic changes
3. Morphological specializations that produce from dendrites
– 0.5-2 mm
– 1-10 spinner per micron
4. Excite synapses
5. PSD95: scaffolding protein that regulates the trafficking of glutamate receptors to the postsynaptic membrane. It also clusters receptors, potassium channels, and signaling proteins during the formation of dendritic spines

Types of Dendritic Spines:
1. Dendritic spines are tiny protrusions(projection) that receive excitatory synaptic input and compartmentalize postsynaptic responses
2. Heterogeneousin size and shape, and modifiable by activity and experience, dendritic spines have long been thought to provide a morphological basis for synaptic plasticity - presynaptic activity the more active the synapse the more likely it will be morphologically mature, a length of a dendrite with multiple spine subtypes like Filopodia is immature and more aged or mature like mushroom
3. Dendritic spines have been classified by shape, and there are numerous classifications of these: as filopodia, long thin, thin, stubby, mushroom - and branched

Question 16

Changes in Dendritic Spines Over Time:

In the developing brain, dendrites first develop devoid of ????

Dynamic, finger-like ??? called ????? begin to project from dendrites during the ????? period
– Filopodia are??????

As development continues, filopodia give way to ????????

Dendritic spines formed during early postnatal life undergo????????? highest number when??????

Early postnatal (filopodia) → WHAT→ WHAT→ WHAT → WHAT → WHAT→ Adulthood

Sensory Experience: Sensory experience influences spines - sensory deprivation ???????

Learning: Experience affects spine dynamics - motor learning protomes spine formation followed by spine elimination; repeated motor training indices ??????????????

Altered Spine Development and/or Maintenance Contributes to Disease
1. Spinogenesis: ???
2. Spine pruning: ????
3. Spine maintenance: ????
4. Which 3 Diseases?

Answer 16

Changes in Dendritic Spines Over Time:

In the developing brain, dendrites first develop devoid of spines and synapses

Dynamic, finger-like protrusions(projection) called filopodia begin to project from dendrites during the synaptogenesis period
– Filopodia are highly mobile, extending and retracting to form synapses - search around for a presynaptic neuron to synapse with

As development continues, filopodia give way to dendritic spines

Dendritic spines formed during early postnatal life undergo pruning, which eliminates roughly 50% of the synapses/spines. - highest number at age 2

Early postnatal (filopodia) → spinogenesis (formation of immature spines) → Adolescence → spine pruning (refining synapses) → Early Adulthood → Maintenance (strength and maintain) → Adulthood

Sensory Experience: Sensory experience influences spines - sensory deprivation prevents spine pruning, novel sensory experience promotes dendritic spine formation and stabilization of new spine

Learning: Experience affects spine dynamics - motor learning protomes spine formation followed by spine elimination; repeated motor training indices coordinated spine formation in cultures. Fear conditioning increases paine elimination in the frontal association cortex and increases pine formation in primary auditory cortex.

Altered Spine Development and/or Maintenance Contributes to Disease
1. Spinogenesis: formation of new and immature spines
2. Spine pruning: refining synapses and getting rid of unused spines
3. Spine maintenance: strength and maintain and keeping established mature spines
4. Tuberous sclerosis, Rett syndrome, down syndrome

Question 17

Location of Excitatory vs. Inhibitory synapses:
1. Spines: Excitatory Synapses - ???
2. Shafts and Cell Bodies: Inhibitory Synapses - ????

Synaptic Plasticity:
1. The ability of the synapse (connection) between ????
2. The ability of synapses to become stronger or weaker over time in response to ????
3. Can be short ????

What is the Function of Synaptic Plasticity?
1. Controls how effectively neurons communicate - how ????
2. Ramon y Cajal hypothesized that the anatomical junctions between neurons (synapses - coined by Sherrington in 1897) stored ?????

Hebbian Plasticity - brain changes with experiences:
1. “When an axon of cell A is near enough to excite B and repeatedly or persistently takes part in firing it, some growth process or metabolic change takes place in one or both cells such that A’s ?????”
2. Cells that fire together ?????
3. Canadian neuropsychologist Donald Hebb
4. 1949 The Organization of Behavior

Hebbian Postulate:
1) Temporal order: cell A evokes the firing of cell B, so the presynaptic cell A is active before ???
2) Cooperation: Cell A needs to act in cooperation with other ????
3) Strengthening is synapse specific, which means that ???? “neurons that wire together fire together” - even on same ?????
4) Unstable: ?????

Not mentioned by Hebb but extremely relevant:
1. Weakening of the connection is never mentioned or implied though?????? “neurons out of sync lose their ??????
2. Treats all synapses as if they are equal: ??????? This is NOT true

Answer 17

Location of Excitatory vs. Inhibitory synapses:
1. Spines: Excitatory Synapses - axodendretic and glutamatergic
2. Shafts and Cell Bodies: Inhibitory Synapses - dendritic shafts closer to cell body so axosomatic

Synaptic Plasticity:
1. The ability of the synapse (connection) between neuron and effector to change in strength.
2. The ability of synapses to become stronger or weaker over time in response to increases or decreases in their activity, respectively.
3. Can be short term or long term.

What is the Function of Synaptic Plasticity?
1. Controls how effectively neurons communicate - how much pre input is needed for a post response
2. Ramon y Cajal hypothesized that the anatomical junctions between neurons (synapses - coined by Sherrington in 1897) stored memories as changes in efficacy or strength of the connections.

Hebbian Plasticity - brian changes with experiences:
1. “When an axon of cell A is near enough to excite B and repeatedly or persistently takes part in firing it, some growth process or metabolic change takes place in one or both cells such that A’s efficiency, as one of the cells firing B, is increased.”
2. Cells that fire together wire together
3. Canadian neuropsychologist Donald Hebb
4. 1949 The Organization of Behavior

Hebbian Postulate:
1) Temporal order : cell A evokes the firing of cell B, so the presynaptic cell A is active before the postsynaptic cell.
2) Cooperation: Cell A needs to act in cooperation with other presynaptic cells to induce synaptic strength.
3) Strengthening is synapse specific, which means that only active synapses are affected by the rules. “neurons that wire together fire together” - even on same post cell not all synapses will be strengthened
4) Unstable: Not permanent - constantly changing

Not mentioned by Hebb but extremely relevant:
1. Weakening of the connection is never mentioned or implied though now it is clear that this occurs: “neurons out of sync lose their link” - we prune that synapse
2. Treats all synapses as if they are equal: (i.e., no distinction between dendritic, axonal and soma connections). This is NOT true

Question 18

Hebbian Plasticity:

Synaptic plasticity is classified according to the duration over which the effect persists:
1. Short Term Plasticity:
– Facilitation appears ??????
– Depression recovers and ????
– Post-tetanic potentiation can last for more than ?????/
– These changes last milliseconds to seconds to ?????
2. Long term Plasticity:
– Long Term ?
– Long Term ?
– LTP and LTD last ???
3. Homeostatic plasticity:
– Activity-???

In-class Question:
What brain area are Medium Spiny Neurons located in? What NT do they release? What NT do they respond to?

Predict: what do you think cocaine administration will do to dendritic spine density in MSNs?

What do you think will happen to spine density during withdrawal? What do you think the behavioral effect of this would be?

Answer 18

Hebbian Plasticity:

Synaptic plasticity is classified according to the duration over which the effect persists:
1. Short Term Plasticity:
– Facilitation appears instantly, and is of short duration (100 ms)
– Depression recovers and Augmentation(increasing the size) dissipates within 10 seconds
– Post-tetanic potentiation can last for more than 10 minutes
– These changes last milliseconds to seconds to minutes
2. Long term Plasticity:
– Long Term Potentiation
– Long Term Depression
– LTP and LTD last minutes to hours
3. Homeostatic plasticity:
– Activity-Dependent plasticity

In-class Question:
– Respond to DA, striatum, release GABA
– Predict: Increased dendritic spine
– Derive of new spines facilitates rewarding properties of cocaine during withdrawal can facilitate drug seeking

Question 19

Short Term Plasticity - short forms of plasticity lasting sec to mins

Forms of Short-Term Plasticity - a lot of these mechanisms are ????????

STP contributes to the modulation of neural ????

Timeline: ????

Facilitation:
1. Rapid increase in synaptic strength that occurs when ??????
2. Thought to be due to prolonged ?????/

Depression:
1. Causes NT release to ?????
2. Depends on the amount of NT released, is likely due to the progressive ????????

Augmentation and Potentiation:
1. Elicited by repeated synaptic activity: serve to ??????
2. Both augmentation and potentiation enhance the ?????
3. Augmentation: ???????
4. Potentiation: ????

Facilitation: Short-Term Strengthening of Synapses - when AP happens in pre neuron Ca entry happens in ms - the mechanisms to remove the Ca is slower
1. The amplitude of the ???????
2. Releases more NT than is normal for 1 AP bc of ?????????
3. Pair of presynaptic APs elicits?????

Answer 19

Short Term Plasticity - short forms of plasticity lasting sec to mins

Forms of Short-Term Plasticity - a lot of these mechanisms are presynaptic

STP contributes to the modulation of neural signaling and information processing in the brain.

Timeline: temporary – milliseconds to minutes

Facilitation:
1. Rapid increase in synaptic strength that occurs when two or more action potentials invade the presynaptic terminal within a few milliseconds of each other
2. Thought to be due to prolonged elevation of presynaptic calcium levels - Increase vesicle fusion and NT release

Depression:
1. Causes NT release to decline during sustained synaptic activity
2. Depends on the amount of NT released, is likely due to the progressive depletion of a pool of synaptic vesicles available for release - decrease NT release bc running out of vesicles ready to be released

Augmentation and Potentiation:
1. Elicited by repeated synaptic activity: serve to increase the amount of transmitter released from presynaptic terminals
2. Both augmentation and potentiation enhance the ability of incoming calcium to trigger fusion of vesicles
3. Augmentation: rises and falls over a few seconds
4. Potentiation: acts over a timescale of tens of seconds to minutes

Facilitation: Short-Term Strengthening of Synapses - when AP happens in pre neuron Ca entry happens in ms - the mechanisms to remove the Ca is slower
1. The amplitude of the postsynaptic response increases when the presynaptic cell is activated several times in quick succession
2. Releases more NT than is normal for 1 AP bc of prolonged Ca in pre terminal and when we have AP happening in pre close together the increase of Ca leads to increase of vesicle release and leads to larger post response
3. Pair of presynaptic APs elicits two EPSPs Second EPSP is larger

Question 20

Short Term Plasticity - short forms of plasticity lasting sec to mins

Facilitation Role at Synapses

Cellular Level:
1. Strength of output as a function of past ?????
2. Dynamic synapses convey information about ???????

Behavioral Level:
1. Critical role in working memory: short-term ?????
2. Information about the initial stimulus is stored by ?????
3. The information can be retrieved by a subsequent sweep of ??????

Residual Calcium Hypothesis:
1. Accumulation of intracellular calcium in the presynaptic terminal results in ?????
2. Calcium entry occurs within 10s of msecs but the mechanism to ?????

In Class Question:
From Behavior to Synapses: Short Term Synaptic: Plasticity in Aplysia californica. Aplysia californica: a marine snail with a simple nervous system of about 20,000 neurons. Has a set of defensive reflexes for withdrawing its gill. Exhibits simple forms of reflexive learning/ Behavioral training leads to changes in the efficacy of synaptic transmission. The Gill Withdrawal Reflex of Aplysia: tactile or electrical stimulation of the siphon or mantle elicits withdrawal of the gill and siphon into the mantle cavity.What do you predict will happen to the strength of gill withdrawal with repeated trials of touching the siphon? What if you paired a shock with the siphon touch?

Answer 20

Cellular Level:
1. Strength of output as a function of past presynaptic activity - bc of the residual Ca in axon terminal from prior AP that was sent
2. Dynamic synapses convey information about both the mean firing rate (frequency of APs) and the temporal history of presynaptic spikes - how active is this synapse

Behavioral Level:
1. Critical role in working memory: short-term storage of information for subsequent manipulation and decision making.
2. Information about the initial stimulus is stored by facilitating synapses(increase AP for the initial thing we are trying to remember) between connected prefrontal cortex cells.
3. The information can be retrieved by a subsequent sweep of activity through the network - residual Ca still present

Residual Calcium Hypothesis:
1. Accumulation of intracellular calcium in the presynaptic terminal results in an enhancement in the number of vesicles released on the second pulse.
2. Calcium entry occurs within 10s of msecs but the mechanism to remove the calcium takes longer (100s of msecs)

In Class Question: Timescale of pre still matters and desensitization

Question 21

Short Term Plasticity - short forms of plasticity lasting sec to mins

Augmentation of Synaptic Transmission - elicited by repeated pre activity:
1. Involved in processing sensory ????
2. Slower phase of ????
3. Increase in synaptic potential amplitude comes on ????
4. Decays over a much longer ????
5. Prolonged stimulation loads nerve terminals with both ????
6. The reduction in the Na+ gradient reduces removal of ????
7. Amplification of residual [Ca2+]I and prolongation ????
8. If persistent enough → ????
9. Potentiation outlasts the initial ????
10. ???? dependent

PTP and the Readily Releasable Pool of Synaptic Vesicles:
1. PTP—once stimulus is gone ????
2. (4–5-s) high-frequency (100 Hz) action ????
3. Recovers slowly from ????
4. Fully releasing the ????

Answer 21

Augmentation of Synaptic Transmission - elicited by repeated pre activity:
1. Involved in processing sensory information, motor control, and memory processing.
2. Slower phase of facilitation
3. Increase in synaptic potential amplitude comes on more slowly than facilitation
4. Decays over a much longer time period (time constant of 5-10s) - compared to ms for facilitation
5. Prolonged stimulation loads nerve terminals with both Na+ and Ca2+
6. The reduction in the Na+ gradient reduces removal of Ca2+ by Na+ /Ca2+
7. Amplification of residual [Ca2+]I and prolongation of its removal
8. If persistent enough → Post-tetanic potentiation
9. Potentiation outlasts the initial tetanic stimulation
10. Ca2+ dependent

PTP and the Readily Releasable Pool of Synaptic Vesicles:
1. PTP—once stimulus is gone the change in release probability persists
2. (4–5-s) high-frequency (100 Hz) action potential tetanic stimulation
3. Recovers slowly from depletion - reserved pool and is Ca2+ dependent
4. Fully releasing the RRP of vesicles

Question 22

Short Term Plasticity - short forms of plasticity lasting sec to mins

Post-tetanic Potentiation:
1. Cellular Level:
A. Enhanced release of ????
B. Increase in ????
C. Even after a pre neuron is no longer sending AP the depo and residual Ca is ????
D. QC = EPSPS/mEPSPS - measure if ????
E. Calcium-dependent
– Increase in mobilization of ????
– Increased activation of ????
2. Behavioral Level: zippering together
A. Muscle: overcome ????
B. Hypothalamus: increase in ????

Short-term Depression:
1. Short-term weakening of ????
2. Mechanism:
A. Depletion of ????
B. Inactivation of presynaptic calcium currents
– complex voltage-dependence of ????
– slow rates of ????
3. Dynamic gain-control mechanism that allows equal ????
4. Short term decrease in NT release and subsequent ????

Answer 22

Post-tetanic Potentiation:
1. Cellular Level:
A. Enhanced release of vesicular pool that outlasts initial stimulus
B. Increase in quantal content
C. Even after a pre neuron is no longer sending AP the dep and residual Ca is so high that vesicles release continues for tens of seconds
D. QC = EPSPS/mEPSPS - measure if ho many vesicle (quanta) of NT are released per EPSPS
E. Calcium-dependent
– Increase in mobilization of vesicles to release sites - synaptotagmin of activation
– Increased activation of SNARE Complex
2. Behavioral Level: zippering together
A. Muscle: overcome use fatigue
B. Hypothalamus: increase in food intake - PTP can induce high food intake

Short-term Depression:
1. Short-term weakening of synapses
2. Mechanism:
A. Depletion of vesicular pool during sustained neuronal activity - we can deplete the RRP and deplete the recycling pool
B. Inactivation of presynaptic calcium currents
– complex voltage-dependence of the inactivation mechanism - VGCC
– slow rates of recovery
3. Dynamic gain-control mechanism that allows equal percentage rate changes on rapidly and slowly firing afferents to produce equal postsynaptic responses.
4. Short term decrease in NT release and subsequent post response due to VGCC inactivation and vesicle depletion

Question 23

Short Term Plasticity - short forms of plasticity lasting sec to mins

Calcium-dependence: increase or decrease ????

Stimulus-dependent: AP frequency at ????/

Vesicle Release Probability (increase or decrease): ?????

Multiple forms of STP coexist at the same synapse:
1. Relative contributions ???
2. Cause dynamic changes as a consequence of recent history - ?????/
3. Changes in synaptic activity over ?????

Answer 23

Calcium-dependence: increase or decrease of Ca affected release

Stimulus-dependent: AP frequency at pre affects timeline (facilities ms, argument 5-10s, potent 10st)

Vesicle Release Probability (increase or decrease): increase is ST Potent and decrease is ST depo

Multiple forms of STP coexist at the same synapse:
1. Relative contributions vary
2. Cause dynamic changes as a consequence of recent history - dynamic we can have one type that swiftly turns into another start
3. Changes in synaptic activity over msec-min time course

Question 24

Long Term Plasticity LTP and LTD

CNS areas with Long-term Plasticity

In the CNS, repetitive activity produces changes(long term) in synaptic efficiency that last much longer than seen at ?????

Hippocampal: LTP best studied of any plasticity, hippocampal LTP important for ????
Input-specific: changes in synapse strength occurs only at ???????

Cortex: ???????

Amygdala: ????

Cerebellum: ?????

Spinal cord: ??????

LTP at Schaffer Collateral-CA1 Synapse is an attractive neural mechanism for information storage:
1. Cellular Level:
A. Strong, ????
B. Input-????
C. Asso???
D. Maintained over a ????
2. Behavioral Level: ???

Answer 24

In the CNS, repetitive activity produces changes(long term) in synaptic efficiency that last much longer than seen at peripheral synapses – ranging from minutes to hours

Hippocampal: LTP best studied of any plasticity, hippocampal LTP important for memory
Input-specific: changes in synapse strength occurs only at postsynaptic targets specifically stimulated by a presynaptic target. Not entire area, only specific neurons in that circuit - EPSP and glutamatergic

Cortex: LTP and LTD at pyramidal synapses

Amygdala: LTP closely linked to fear conditioning

Cerebellum: LTD of purkinje

Spinal cord: LTP at dorsal horn neurons - chronic pain

LTP at Schaffer Collateral-CA1 Synapse is an attractive neural mechanism for information storage:
1. Cellular Level:
A. Strong, coincident activity in both pre- and postsynaptic cells (<100 ms apart) (Hebb’s prediction)
B. Input-specific
C. Associativity
D. Maintained over a long period of time
2. Behavioral Level: Long lasting storage of information

Question 25

Long Term Plasticity LTP and LTD

Signaling Mechanisms Underlying LTP in Hippocampus - timing of diff components is key to the development of LTP - things must occur in specific order and diff components are responsible for either the Induction of maintenance of LTP
1. Molecular Coincidence Detector: Which receptor → CAMKII (Ca calmodulin kinase 2) → Increased Insertion of ?????→ Gene ?????
2. Induction: starts series of ?????
3. Maintenance: long lasting synaptic changes due to ???????

The NMDA receptor channel can open only during depolarization of the postsynaptic neuron from its normal resting potential - Insertion of More AMPA Receptors - Molecular Coincidence Detector: WHICH receptor
1. At resting potential - After glutamate binds and glycine as co-agnaoist the pore opens BUT Mg present in ECF ends up ???????
2. During post depo - In addition to Na Ca also enters this activates ?????
3. The expression of LTP replies on ?????
4. There is What mediated insertion of AMPAR into post membrane. These ??????
5. This makes it even more likely that more?????
6. Eventually the neuron starts it makes more ????????
7. Ca entry is key modulator activated protein incase ?????

Answer 25

Signaling Mechanisms Underlying LTP in Hippocampus - timing of diff components is key to the development of LTP - things must occur in specific order and diff components are responsible for either the Induction of maintenance of LTP
1. Molecular Coincidence Detector: NMDA receptor → CAMKII (Ca calmodulin kinase 2) → Increased Insertion of AMPA receptors (first already existing but in stored vesicles and then new gene transcription) → Gene regulation (protein-synthesis dependent maintenance)
2. Induction: starts series of intracellular cascades that eventually lead to gene changes
3. Maintenance: long lasting synaptic changes due to new proteins

The NMDA receptor channel can open only during depolarization of the postsynaptic neuron from its normal resting potential - Insertion of More AMPA Receptors - Molecular Coincidence Detector: NMDA receptor
1. At resting potential - After glutamate binds and glycine as co-agnaoisty the pore opens BUT Mg present in ECF ends up blocking the pore, it takes sufficient membrane depo to repel the mg out of the NMDAR pore then ions can flow in
2. During post depo - In addition to Na Ca also enters this activates CAMKII an important second messengers for gene transcription
3. The expression of LTP replies on dynamic changes in AMPARs
4. There is synaptotagmin mediated insertion of AMPAR inti post membrane. These AMPAR come from intracellular recycling endosomes. The resulting increase in AMPAR on post increase response of post to pre input
5. This makes it even more likely that more Ca enter via NMDAR
6. Eventually the neuron starts it makes more AMPAR to insert into the membrane
7. Ca entry is key modulator activated protein incase C and CAMKII

Question 26

Long Term Plasticity LTP and LTD

Summary: LTP

Physiologically relevant stimulation – rhythms ????

Input ????

Coordinated activity between the ????

Coincidence detection – ????

Calcium as second messenger ????

Insertion of AMPA receptors into ????

Transcriptional regulation ????

Answer 26

Physiologically relevant stimulation – Theta rhythms (200 Hz bursts at 200 msec intervals)

Input specificity

Coordinated activity between the pre and post-synaptic cell

Coincidence detection – NMDA receptor

Calcium as second messenger (CAM KII protein kinase activation)

Insertion of AMPA receptors into the postsynaptic membrane (induction)

Transcriptional regulation (protein-synthesis dependent maintenance)