learning & memory 2. synaptic plasticity
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Learning & Memory 2. Synaptic plasticity
Bi/CNS 150 Lecture 21 Monday November 16, 2015 Learning &
Memory 2.Synaptic plasticity Henry Lester Chapters 66, 67 The
Hebbian Synapse From The Organization of Behavior by Donald Hebb,
1949: When an axon of cell A is near enough to excite cell 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.
Hebb postulated that this behavior of synapses in neuronal networks
would permit the networks to store memories. A Hebbian synapse is a
coincidence detector NMDA receptors, back-propagating action
potentials, and summation of epsps May be the components that
confer Hebbian behavior on the synapse. Synaptic Plasticity in the
Hippocampus, Cortex, and Striatum
Synapses in severalbrain regions are tightly regulated. Regulation
helps to maintain homeostatic balance It also serves to process and
store information in neural circuits. The chemical synapse is a
biophysical machine, specialized to function on a time scale of
milliseconds and a distance scale < 1 m. But **also** to adapt
to changing needs and activity levels. Homeostasis, adaptation,
plasticity, compensation: These are summary processes, not
mechanisms. They are best used as adjectives. We do not say, a
synapse changes because of homeostasis; We say, a synapse changes
because of a homeostatic process During the 21st century,
scientists will continue to discover . . . the molecular
instantiations of homeostatic processes. The Hippocampusa Key
Region for Memory and Learning
toothlike Cornu Ammonis, latin Ammons (Egyptian ram-like god) horn
Perforates from neocortex to archecortex Figure 67-2 Codes for
Spatial Awareness in the Hippocampal Formation:
Place Cells in CA1 Grid Cells in Entorhinal Cortex Nobel Prize 2014
Figure 67-2 Figure Grid cell (entorhinal cortex) Place cell (CA1)
Many synapses occur on spines, which form on dendritic
shafts.
Spines are dynamic, plastic, changeable. Reconstruction of
dendritic spines from serial EM pictures in hippocampus Atlas of
Ultrastructural Neurocytology, Kristen Harris lab Electron
micrograph of hippocampal synapse
From previous lectures 400 nm Electron micrograph of hippocampal
synapse Map of micrograph to the left Control of Synaptic
Plasticity by NMDA Receptors
The central role of Ca2+ in initiation of long-term plastic changes
The Ca2+ hypothesis for control of synaptic plasticity We measure
cytosolic Ca2+ with fluorescent dyes. Control of postsynaptic Ca2+
by spike timing Review of the NMDA receptor Gating (coincidence
detection) Ion selectivity (Na+, K+, Ca2+) Kinetics, NMDA receptors
are slower than AMPA receptors Pharmacology The NMDA receptor is
also a scaffold. The postsynaptic density LTP and LTD are triggered
by Ca2+-sensitive signaling machinery located near the mouth of the
NMDA receptor. Critical components of the postsynaptic density
Biochemical pathways mediating changes in synaptic strength NMDA
receptors are coincidence detectors.
From previous lectures NMDA receptors are coincidence detectors.
Their channel opens only when two events happen concurrently: 1.
Glutamate binds 2. Strong postsynaptic membrane depolarization (as
by an action potential) The depolarization relieves block by Mg2+
Modified from Zigmond et al. (Eds.) Fundamental Neuroscience,
Sinauer (1999) The coincidence readout: NMDA receptors are very
permeable to Ca2+ Signaling Complexes in the Postsynaptic
Density
Mary Kennedy Mechanism of Activation of CaMKII, and
Autophosphorylation
Ca2+/calmodulin-dependent protein kinase CaMKII is activated by the
calcium-binding protein calmodulin Autophosphorylation of CaMKII
can prolong its activation by calcium. Presynaptic vs.
Postsynaptic
I. The size of synaptic potentials can be modulated: by regulating
the number of number of vesicles (quanta) released. by regulating
the quantal size, the current generated by a released quantum at
the postsynaptic membrane. II. Short-term modulation (ms - min) The
mechanisms of these forms of modulation are usually presynaptic.
Paired-pulse facilitation (~10 to 100 ms) Synaptic depression (50
ms to min) Post-tetanic potentiation (min) Long-term plasticity The
mechanisms are usually both pre- and postsynaptic LTP(30 min to yr)
LTD (30 min to yr) Paired Pulse Facilitation
Paired activations of a synapse onto a Layer 2/3 cortical
neuron.Residual Ca2+ in presynaptic terminal for 10 to 100 ms after
the first stimulus increases probability of release. Short-term
Synaptic Depression
Successive stimuli at 50 Hz Both the rate and the steady-state
level of depression depend on the stimulus frequency. Cook et
al.Nature 421, (2003) Post-Tetanic Potentiation
PTP presumably arises from a large accumulation of Ca2+ in the
terminal caused by a high frequency tetanic stimulation. Recording
Long-Term Potentiation in a Hippocampal Slice
Stimulation frequencies that produce LTP usually range from ~50 to
200 Hz. Long-term Synaptic Plasticity
Frequency-dependent Long-term Potentiation (LTP) This term actually
represents many mechanisms, all of which result in strengthening of
the synapse for varying periods of time following tetanic
stimulation. The mechanisms for LTP lasting 30 min to a few hr do
not require new protein synthesis The mechanisms for LTP lasting
longer than a few hr do require protein synthesis.
Frequency-dependent Long-term Depression (LTD) This term also
represents many mechanisms LTD, like LTP, modifies circuits to
store information. Spike-timing dependent synaptic plasticity
(STDP) presumably arises from the same set of mechanisms as LTP and
LTD. Postsynaptic Calcium Levels and Synaptic Plasticity
1.Level and timing of Ca2+ rise in spine determines LTD or LTP. Low
frequency synaptic firing (~5 Hz) produces LTD; high frequency
synaptic firing (~50 to 100 Hz) produces LTP. The same Ca2+ rules
may underlie spike-timing-dependent synaptic plasticity (STDP).
Recording LTD in the Hippocampus
Stimulation frequencies usually range from 1 to 10 Hz. Two cellular
processes underlie the major changes during LTP and LTD
Insertion of AMPA receptors into the postsynaptic membrane (LTP);
or their removal from the postsynaptic membrane (LTD). 2.Growth or
shrinkage of the spine via reshaping of the actin cytoskeleton. LTP
is probably input specific
Figure 67-6 Spike-timing Dependent Synaptic Plasticity
Pre- fires 5-30 ms before post LTP Pre- fires 5-30 ms after post
LTD These recordings were made on cultured neurons anti-Hebbian
Hebbian From Bi and Poo J. Neurosci. 18, (1998) Supralinear influx
of Ca2+ during paired EPSP and AP
From Schiller, Schiller and Clapham, Nature Neuroscience 1, 114
(1998) Increased quantal size usually arises from additional
receptors
Early LTP, < 2 h Increased quantal size usually arises from
additional receptors Figure 67-8 Late LTP, > 2 h Increased
number of quanta released per presynaptic action potential Protein
synthesis is involved Figure 67-8 Overall View of NMDA-dependent
LTP in hippocampus (CA3-CA1 synapse)
Gene activation via CREB / CRE Dendritic protein synthesis
Retrograde signal (nitric oxide?) Cytoskeleton changes? Figure 67-9
Targets of calcium influx through the NMDA receptor Role of CaMKII
in LTP 1.Calcium ion flows through the activated NMDA receptor.
2.One of its targets is calcium/calmodulin-regulated Protein Kinase
II (CaMKII). 3.CaMKII can phosphorylate the subunits of the AMPA
receptor. The phosphorylated AMPA receptor has a larger current
This is likely one mechanism of relatively short LTP (30 min or
so). 4. CaMKII initiates a process that results in addition of new
AMPA receptors to the synapse This process may be developmentally
important It likely also contributes to longer lasting LTP. 5.
Helps regulate processes that re-arrange and enlarge the
cytoskeleton. Role of Calcineurin in LTD
1.Calcium ion flows through the activated NMDA receptor. 2.One of
its targets is calcineurin (or protein phosphatase 2B), a
Ca2+/CaM-dependent protein phosphatase. 3.Calcineurin regulates an
inhibitor (Inhibitor 1) of a more general protein phosphatase
called phosphatase 1. Inhibition of calcineurin blocks induction of
LTD LTD results from removal of AMPA receptors by endocytosis. One
popular hypothesis is that the direction of long-term changes in
synaptic strength depends on the relative levels of activation of
CaMKII and calcineurin. Role of Calcineurin in LTD
1.Ca2+ flows through the activated NMDA receptor. 2.One of its
targets is calcineurin (or protein phosphatase 2B), a
Ca2+/CaM-dependent protein phosphatase. 3.Calcineurin regulates an
inhibitor (Inhibitor 1) of a more general protein phosphatase
called phosphatase 1. Inhibition of calcineurin blocks induction of
LTD LTD results from removal of AMPA receptors by endocytosis. One
popular hypothesis: e direction of long-term changes in synaptic
strength depends on the relative levels of activation of CaMKII and
calcineurin. Figure 67-17 Distinct Molecular Bases of Long-Term
Potentiation at
Three Synapses in Hippocampus Figure 67-3 Epigenetic Changes in
Chromatin Structure may also Participate in Long-Term Memory
Phosphorylation of CREB-1 Recruits CREB Binding Protein (CBP-1) CBP
acetylates lysine(+) resides on histones Histones release DNA(-)
Allow transcription during late LTP LTP changes DNA
methyltransferases (DNMT) This recruits methyl-CpG binding proteins
(Me-CpG-BP) This recruits histone deacetylases (HDAC), which remove
actyl groups Figure 67-18 This allows CREB-2 binding, which
represses transciption Figure 67-18 Henry Lestersoffice hours 1:15
2 M, F
Red Door End of lecture 21 Spike-timing Dependent Plasticity in
Cortical Neurons
Dual whole-cell patch recordings from neurons in cortical slices
from day old rats(Markram et al., Science 275, 213 (1997) Signals
in long-term depression
Dominant negative Figure 67-17 NMDA-Dependent Long-Term
Potentiation in the Hippocampus
Stim. Record The third synapse in thetri-synaptic pathway
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