located within the medial temporal lobe of the brain. It
forms part of the limbic system
Hippocampal Pathways
Hippocampal Function
CA1 region of the hippocampus is vital for some forms of learning
Hippocampus is responsible for the acquisition of
memory with particular emphasis on spatial memory
maintains a neural representation of spatial environment
Presynaptic mechanisms of plasticity
Short-term Plasticity
3 types of Short-term plasticity
Paired Pulse Depression
Synapses that release transmitter at a high
release probability
3 factors for reduced release
Depletion of the proportion of vesicles that
are in the Readily Releasable Pool (RRP)
Release site innactivation due to vesicular membrane proteins
interfering with membrane consistency/ protein interactions
Decreased calcium influx. Decreased activity of Ca/
Calmodulin complex. P-type Ca Channels not activated
Paired Pulse Potentiation
Paired Pulse Facilitation
Hippocampal mossy fibres participate in a lot
of PPF at the synapse to CA3 Pyramidal cells.
Low Release probability
Metabotropic receptors are the "brakes" the cell applies to ensure that
there is a limit to the magnitude of frequency-dependent facillitation
Fibres contain adenosine A1 GPCRs on the presynaptic cell. These
receptors have an inhibitory effect on glutamate release
Mossy fibres also express metabatropic Glutamate receptors (mGluR 2 or 3) which
also suppress glutamate release at the synapse by inhibiting calcium entry
negative feedback to stop over excitation/ glutamate
release as Glutamate spills over to activate mGluR
Activation of G protein-coupled receptors can transiently inhibit vesicular release through the
release of Gβγ which binds to both voltage-dependent calcium channels to reduce calcium influx, and
directly to the C-terminus region of the SNARE protein SNAP-25
Pairs of pulses delivered at
intervals of several tens of
milliseconds
Unlike LTD or LTP, the effects last for a
maximum of a couple of seconds
Calcium dependency
Short-term facilitation
Transmitter release
Transient increases in [Ca2+]i, in close proximity to
voltage-gated Ca channels, drive phasic transmitter
release. This contributes to depolarisation
Ca2+ channels will remain open until repolarisation occurs
Calcium signal will reduce quickly due to diffusion
Residual Calcium signals remain (at a concentration of ~500nM) as Calcuim
buffering and extrusion (active transport out of the cell or into intracellular
stores) are slow therefore there is a slow signal decay
Residual calcium builds up during repetitive stimulation (5-10Hz)
Asynchronous signalling
Synchrony
Residual calcium may serve as a mechanism for
short-term plasticity within neuronal circuits
[Ca2+] levels in the tens of micromolar range
Mechanism of transmitter release
How many molecules of Ca2+ are needed for Synaptotagmin to perform vesicular exocytosis??
Ca sensitive protein which, when bound to embedded
proteins, forms the SNARE complex
2 models
5-site
Does not account for the calcuim concentration range at
which exocytosis of vesicles occurs
may therefore require activation at an allosteric site in low calcium concentrations
2-site 5-site
2-site filled
Possible at low concentrations of calcium, slow calcium sensor
Asynchronous
5-site filled
only possible at high concentrations, fast calcium sensor
Synchronus
Synchrony
Long-term
mGluR may also have a long-term presynaptic effect
Activation of G protein-coupled receptors can transiently inhibit vesicular release through the
release of Gβγ which binds to both voltage-dependent calcium channels to reduce calcium influx, and
directly to the C-terminus region of the SNARE protein SNAP-25.
Alford et al. 2013 showed that it is necessary but not sufficient to produce LTD alone
Presynaptic LTP in the Mossy fibre/ CA3 pyramidal synapse
Increases in PRESYNAPTIC Calcium
post-synaptic calcium has a very small role
N-type, P/Q-type and R-type Calcium Channels have all been
implemented as important for calcium entry
N or P/Q type are sufficient for LTP induction
Access to AC and release machinery
R-type channels
Lower threshold for LTP induction
Does not have access to the release machinery
Preferential access to
Adenylyl Cyclase (AC)
Through
Calmodulin/Ca
complex
Amplitude of EPSP does not change significantly between
WT and mice with a R-type subunit knockout
Enhancement of neurotransmitter release involves enhanced Ca coupling to SNARE complex
Post synaptic Mechanisms of Plasticity
Long Term Potentiation (LTP)
Molecular mechanisms
of long-term
potentiation
Signalling Cascades
Increased [Ca2+]i allows for Calmodulin to bind 4Ca2+ cations
Ca/Calmodulin complex also activates membrane-bound Adenylyl Cyclase
ATP > cAMP
cAMP bind and activates Phosphokinase A (PKA)
PKA traslocates into the nucleus
Kinases Activate CREB1 (cAMP response element binding protein)
CREB activates CRE (cAMP response element)
Calcium-regulated gene expression of certain growth factors that may
enable De novo spine formation
PKA can also activate MAPK (mitogen activated protein kinase)
MAPK translocates into the nucleus
Signal transduction
NMDA receptors
NMDA receptors open with Glutamate
binding on the extracellular domain.
"coincidence detectors" as require Mg
block removal and glutamate
Influx of Ca2+, Na+ and efflux of K+
Intracellular Ca2+ increases with opening of
NMDA channels
AMPA Receptors
On ligand (aglutamate) binding,
AMPA receptors open, allowing for
sodium influx and potassium eflux
Intracellular concentrations of Na are higher than
external concentrations. The net possitive charge
intracellularly resultis in the magnesium block in
NMDA channels to be removed
Increased [Ca2+]i allows for the Ca/Calmodulin complex to form
Ca/Calmodulin activates CAMKII by phosphorylation ***
CAMKII phosphorylates Stargazin scaffold protein
PSD95 can therefore bind and can relocate the AMPA receptor to the
post-synaptic density
CAMKII also phosphorylates the GluR1
subunit at Serine 831
Increases the Conductance of the AMPA Receptor
How is LTP induced?
Pyramidal neurons fire at a frequency of 5Hz. This is known as "theta rhythm"
Theta rhythm
Three trains of stimuli that are 20 seconds apart
Each train composed of 10 stimulus epochs which are delivered at 5Hz (i.e. 200ms apart)
each epoch is made up of four individual stimuli at 100Hz
during exploration (spatial mapping)
Discovery
Raising the frequency of firin from 0.5Hz to 15Hz
follow grey lines
Baseline at 0.5 Hz
Initial facilitation
of EPSP at 15 Hz
Rapid decline past
baseline
Gradual rise to an
increased baseline mV
Properties
4 major properties/ conditions neccessary for LTP
Cooperativity
LTP can be induced by a single, strong, tetanic signal to a synapse
OR via weaker stimulation of may cooperating pathways
Associativity
the contributing fibres need to be active together
information from the two contributing sources must coincide
both temporally and spatially
Weak tetanic stimulus in one location will be
insufficient in producing LTP, but paired with a
strong signal in another location can induce LTP
Input specificty
LTP will only occur at synapses which receive tetanic stimulation,
even if it is within the same cell, other synapses which do not
recieve stimulation will not share in synaptic enhancement (i.e.
increased expression of AMPA or NMDA receptors)
Persistance
LTP is also persistent, it can last for several hours and even for many
months suggesting that a sustained physiological change
accompanies memory formation
'Hebb Rule' = if both pre and post-synaptic cell are excited at the same time, the synaptic connection is strengthened
Glutamate is the main excitatory
neurotransmitter in the synaptic transmission
between Schaffer Collateral fibres and the CA1
pyramidal cells