Molecular Mechanisms Of Learning And Memory Flashcards
Repetitive activation of an afferent pathway to the hippocampus increases response where?
Pyramidal cells
Two phases of LTP
Early- insertion of receptors from vesicle stores (min/hrs)
Late- modification of gene expression and structural changes (hrs/days)
What are silent synapses
Synapses only have NMDAR. Few or no AMPA can be woken up by LTP
What molecules needed for AMPA insertion
High Ca- activates calmodulin and CAMKII
AMPA phosphorylation and exocytosis
Presynaptic LTP pathway
Repetitive synaptic activity leads to presynaptic Ca entry - AC - cAMP - PKA - Rab3a and RIM1 (coordinate exocytosis) - exocytosis of glutamate
How are AMPAR removed- LTD
- dynamin/clathrin mediated endocytosis
Name two other LTD mechanisms
mGluR
eCB
mGluR pathway
Glu binds to mGluR postsynaptic - triggers AMPAR internalization
- process requires rapid protein synthesis (mechanism)
First observed at parallel fibre Purkinje cell synapse
eCB LTD pathway
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
Main postsynaptic receptor in cerebellum
mGluR
How do cannabinoids work
Mostly acyl chain- high hydrophobic - diffuse out of neuron
- travel retrograde
Effect of cannabis on body? location of binding?
Bind to CBR - found in hippocampus and substantia nigra (reward, addiction)
- can permanently effect learning and memory
Explain late events of LTP. Why are they important?
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
How to go from LTP to LTD
Late stages of LTP removed first. Early stages removed next
- internalize Cadherins
Memory formation in hippocampus
Synapses between excitatory neurons form a new circuit within seconds of event
Long term memory storage location
Temporal lobe
when do synapses weaken
Rlease of NT does not produce an EPSP that reaches threshold
- synapse weakens, circuit may disappear
Experimental evidence for LTP link to learning and memory
- 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)
Place cell experiment
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
Mossy fibres
High frequency
Constant
Multiple sources
Indirect synapses
Climbing fiber
Low frequency
Inferior olive nucleus
Provide input when error (executed doesnt equal intended)
- fires with error
Where are climbing fibres, mossy fibres located
Cerebellum
Function of cerebellum
Oversees if movement executed is equal to movement intended
- important in motor learning
Role purkinje fibres
Sole output of cerebellum. Mossy and climbing send info here
Role of climbing and mossy
Input to purkinje provide Ca that allows LTD when movement is incorrect (we don’t want to strengthen that pathway)
Specific what purkinje cells are and their input
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)
When do parallel fibers change strength
Only if they are active at same time as climbing fiber
How can EPSPs generated by parallel fibers become smaller
When both parallel fibers and climbing fiber were coactivated at low frequencies
When does the cerebellum have lots of mGluR
Function in motor learning. using LTD to reduce strength of synapses to pathways with incorrect execution of intended action
When is LTD induced in cerebellum
When mossy and climbing fire at same time at low frequency (low Ca release supports LTD)
Name diseases with links to LTP/LTD impairment explain main ones
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
Drugs of abuse alter synaptic function and plasticity where?
Ventral Tegmental Area- part of reward system
- increase dopamine
Target of cocaine, amphetamines, ecstasy
Target dopamine transport, increasing dopamine
How do drugs of abuse increase LTP
Increase AMPA/NMDA ratio at glutamatergic synapses
Role of morphine with GABA and Glutamate neurons
GABA- inhibit GABA release therefore decreasing inhibition caused by GABA indirectly increasing excitation
Glutamate- directly increases excitation
Alzheimer’s early and late stages explained
Early- amyloid beta (protein- oligomer) is misfolded and activates mGluR
Late- thinning (smaller) and loss of synapses
Mice experiment linked to addiction? Explain synapse changes
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)
