Molecular Mechanisms Of Learning And Memory

Question 1

Repetitive activation of an afferent pathway to the hippocampus increases response where?

Answer 1

Pyramidal cells

Question 2

Two phases of LTP

Answer 2

Early- insertion of receptors from vesicle stores (min/hrs)
Late- modification of gene expression and structural changes (hrs/days)

Question 3

What are silent synapses

Answer 3

Synapses only have NMDAR. Few or no AMPA can be woken up by LTP

Question 4

What molecules needed for AMPA insertion

Answer 4

High Ca- activates calmodulin and CAMKII
AMPA phosphorylation and exocytosis

Question 5

Presynaptic LTP pathway

Answer 5

Repetitive synaptic activity leads to presynaptic Ca entry - AC - cAMP - PKA - Rab3a and RIM1 (coordinate exocytosis) - exocytosis of glutamate

Question 6

How are AMPAR removed- LTD

Answer 6

• dynamin/clathrin mediated endocytosis

Question 7

Name two other LTD mechanisms

Answer 7

mGluR
eCB

Question 8

mGluR pathway

Answer 8

Glu binds to mGluR postsynaptic - triggers AMPAR internalization
- process requires rapid protein synthesis (mechanism)
First observed at parallel fibre Purkinje cell synapse

Question 9

eCB LTD pathway

Answer 9

Endocannabinoid
mGluR activation by glutamate - PLC and intracellular Ca initiates synthesis of eCB - eCB travels retrograde to bind to presynaptic cannabinoid 1 receptor (CB1R) - depress NT release
- cannabis facilitates this pathway

Question 10

Main postsynaptic receptor in cerebellum

Answer 10

mGluR

Question 11

How do cannabinoids work

Answer 11

Mostly acyl chain- high hydrophobic - diffuse out of neuron
- travel retrograde

Question 12

Effect of cannabis on body? location of binding?

Answer 12

Bind to CBR - found in hippocampus and substantia nigra (reward, addiction)
- can permanently effect learning and memory

Question 13

Explain late events of LTP. Why are they important?

Answer 13

Important- involve structural changes that maintain plasticity
- AMPA anchored by scaffolding proteins- PSD95,cadherins, catenins
- expression levels of scaffolding proteins change (Cadherins increase)
Cadherins- mediate adhesion through interactions across the synaptic membrane and associate with AMPA
Catenins- couple AMPA to cytoskeleton

Question 14

How to go from LTP to LTD

Answer 14

Late stages of LTP removed first. Early stages removed next
- internalize Cadherins

Question 15

Memory formation in hippocampus

Answer 15

Synapses between excitatory neurons form a new circuit within seconds of event

Question 16

Long term memory storage location

Answer 16

Temporal lobe

Question 17

when do synapses weaken

Answer 17

Rlease of NT does not produce an EPSP that reaches threshold
- synapse weakens, circuit may disappear

Question 18

Experimental evidence for LTP link to learning and memory

Answer 18

• in absence of LTP learning and memory is impaired (Giese)
• LTP is increased during fear conditioning (Rogan)
• memories can be inactivated and reactivated with LTD and LTP (Nabavi)

Question 19

Place cell experiment

Answer 19

Place cells are pyramidal neurons within the hippocampus
Single unit recordings from hippocampus show that specific place cells fire when animal in particular location
- put stimuli (light, food) in specific locations, through simultaneous exposure place cells can fire in response to stimulus even when in different location
- link to learning and memory

Question 20

Mossy fibres

Answer 20

High frequency
Constant
Multiple sources
Indirect synapses

Question 21

Climbing fiber

Answer 21

Low frequency

Question 22

Inferior olive nucleus

Answer 22

Provide input when error (executed doesnt equal intended)
- fires with error

Question 23

Where are climbing fibres, mossy fibres located

Answer 23

Cerebellum

Question 24

Function of cerebellum

Answer 24

Oversees if movement executed is equal to movement intended
- important in motor learning

Question 25

Role purkinje fibres

Answer 25

Sole output of cerebellum. Mossy and climbing send info here

Question 26

Role of climbing and mossy

Answer 26

Input to purkinje provide Ca that allows LTD when movement is incorrect (we don’t want to strengthen that pathway)

Question 27

Specific what purkinje cells are and their input

Answer 27

Large GABAergic neurons Receive two types of excitatory input (via synapses) - one climbing fiber (inferior olive nucleus) - 150,000 parallel fibres from tiny granule cells of the cerebellum itself (mossy fibers - granule- parallel)

Question 28

When do parallel fibers change strength

Answer 28

Only if they are active at same time as climbing fiber

Question 29

How can EPSPs generated by parallel fibers become smaller

Answer 29

When both parallel fibers and climbing fiber were coactivated at low frequencies

Question 30

When does the cerebellum have lots of mGluR

Answer 30

Function in motor learning. using LTD to reduce strength of synapses to pathways with incorrect execution of intended action

Question 31

When is LTD induced in cerebellum

Answer 31

When mossy and climbing fire at same time at low frequency (low Ca release supports LTD)

Question 32

Name diseases with links to LTP/LTD impairment explain main ones

Answer 32

Schizophrenia- too much synaptic pruning Alzheimer’s- loss of plasticity, LTP inhibited, LTD induced, neurodegenerative (remove synapses), cognitive decline Addiction (drugs of abuse- cocaine)- excessive plasticity (too much LTP), alter synaptic plasticity in brain’s reward circuitry (dopamine) causing wanting of drug more (behaviour changes) Depression, anxiety, PTSD

Question 33

Drugs of abuse alter synaptic function and plasticity where?

Answer 33

Ventral Tegmental Area- part of reward system - increase dopamine

Question 34

Target of cocaine, amphetamines, ecstasy

Answer 34

Target dopamine transport, increasing dopamine

Question 35

How do drugs of abuse increase LTP

Answer 35

Increase AMPA/NMDA ratio at glutamatergic synapses

Question 36

Role of morphine with GABA and Glutamate neurons

Answer 36

GABA- inhibit GABA release therefore decreasing inhibition caused by GABA indirectly increasing excitation Glutamate- directly increases excitation

Question 37

Alzheimer’s early and late stages explained

Answer 37

Early- amyloid beta (protein- oligomer) is misfolded and activates mGluR Late- thinning (smaller) and loss of synapses

Question 38

Mice experiment linked to addiction? Explain synapse changes

Answer 38

Mice chose cocaine over food - cocaine changes the AMPAR GluA 1/2 heteromer (which is normal and is not permeable to Ca) to AMPAR Glu 1/1 homomers (Cocaine changes AMPAR composition)