lecture 15: synaptic plasticity Flashcards
how are memories stored in the brain
- release of neurotransmitter
- activation of postsynaptic receptors
- trafficking of receptors to the PSD
- local translation of new proteins
- altered gene expression
how do we study learning and memory at the molecular level
–> in vitro
molecular and cellular events
- cells in culture
- acute brain slices (hippocampal slices)
- organotypic brain slices
- others
main components when studying learning and memory
- Glutamate transporter (VGLUT)
- SSV, synapsin
- astrocytes (GFAP) = one of the main support cells, cells in the brain which are described as star shape
- neurons (AMPA-GluA1, glutamate receptors) = really important in synaptic transmission
what tissue do we use for culture to look into learning and memory
to create these we are using really young tissue, so the cells in the culture are young and are forming networks which might not be there in the intact brain
organotypic brain slices
take slice of brain and instead of bathing it in cerebrospinal fluid, just let it be on a membrane, you can start to see more advanced, long term systems such as long term memory
two main types of glutamate receptors in rapid changes (long term potentiation)
AMPA = form sodium channels that depolarise cells and allow for activation of NMDA
NMDA = blocked by magnesium, this is unblocked by calcium from AMPA, allows Ca to flow to the rest of the cell
glutamate receptors
- ionotropic
- metabotropic
ionotropic
form ion channels
mechanism of ligand gated ion channels (glutamate receptors)
- milliseconds
- have intrinsic ion channels, allows flow of ions into the cell
- channel opens to allow influx of efflux of ions
- excitatory
analogy for receptors
- receptors are not islands, they are more like trees
- they have large extracellular domain, created by N terminal, which links to pre synaptic membrane
- and they have long intracellular tails, bind to kinases = when calcium influx comes there is a kinase positioned, ready to react right away
ionotropic glutamate receptors examples
- AMPA
- NMDA
AMPA receptor subtypes
- ligand gated (bind glutamate)
- mediate fast depolarisation
- Na+ channel
NMDA receptor subtypes
- ligand and ion gated
–> bind glutamate
–> require depolarisation to remove Mg2+ from channel
–> therefore, slightly slower response (not as slow as metabotropic receptors) - ca2+ channel and Na+ channel
relevance of AMPA subunits
- made up of 4 subunits that come together to form the ion channel
- relevance of subunits = depending on how you bring the subunits together the channel will have different functions/structures eg: changes what type of ion is allowed through the channel, where the channel opens etc
what are the AMPA-subtypes of glutamate receptors
- GluA1-GluA4 (made of diff subunits labelled 1-4)
- assemble as dimers-of-dimers to form
–> hetero-tetrameric receptors
or
–> homomeric receptors (GluA1) - glutamate binding opens the channel
–> influx of Na+ ions
–> efflux of K+
–> Depolarization
regulation of AMPA-subtype glutamate receptors
- GluA2 subunits undergo RNA editing
–> glutamine - arginine (Q/R) editing
–> prevents ca2+ influx
GluA2-containing AMPARs are Ca2+ impermeable - GluA2-lacking AMPARs are ca2+ permeable
ie: GluA1 homomeric receptors - phosphorylation of GluA1 by CaMKII
–> serine831 enhances single channel conductance - phosphorylation of GluA1 by PKA
–> serine845 enhances open probability and important for retention at the plasma membrane
four classes of neurotransmitters
type 1: amino acids “classical”
- glutamate (excitatory)
- glycine and GABA (inhibitory)
–> found in small synaptic vesicles
type 2: amines and purines
- acetylcholine
- catecholamines (noradrenaline and dopamine)
- histamine
- serotonin
–> found in small synaptic vesicles
type 3: neuropeptides
- opioids, substance P, neuropeptide Y
–> found in large dense core vesicles
type 4: gases
- NO, CO
how does nitric oxide match up to the criteria for neurotransmitters
- NO is a gas derived from arginine
- As it is a gas, NO can not be stored in lipid vesicles
- NO is not released by exocytosis
- NO does not bind to receptors
- NO is not metabolised by hydrolytic enzymes
regulation of nitric oxide
–> control of the synthesis of NO is the key to regulating its activity
- NO is synthesized on demand (neuronal nitric oxide synthase –> nNOS)
- NO diffuses from nerve terminals
>40-300um
> therefore, can act on cells within this range
> modulator
- NO diffuses into cells
- activates second messenger pathways
- inactivated by interaction with substrate
–> NO plays many roles in the CNS and is an important retrograde messenger involved in the long term potentiation model of memory
what are the lasting effects of strong NMDAR activation
- increase in effectiveness of AMPARs at activated synapses
- increase in number of AMPARs at activated synapses
how are AMPARs highly dynamic
- they shuttle into and out of synapses = long lasting changes in synaptic strength
- lateral mobility
–> along the cell surface
–> between synaptic and extra synaptic regions
= increased trafficking to the PSD
= increased retention in the PSD
where are AMPARs synthesised
locally
where are the apparatus required for local protein synthesis found
- polyribosomes are found in spines
- polyribosomes translocate from dendritic shafts to spines in response to activity
- mRNA is found in dendrites
- mRNA is translated in response to activity
–> glutamate receptors are synthesised locally from pre existing mRNA
what does long lasting change require
altered gene expression via CREB phosphorylation and results in growth of dendritic spines
