Synaptic Plasticity. Synaptic Plasticity. I. Synaptic Plasticity (Excitatory spine synapses) Changes in synaptic strength are important for formation of memory. Short Term Plasticity (paired-pulse facilitation, short-term potentiation, synaptic depression)
III.Modulation of firing rate - an example: Accomodation in Hippocampal pyramidal neurons is regulated via Norepinephrine through a G-protein coupled adrenergic receptor linked to cAMP.
The postsynaptic density (PSD) is a specialization of the cytoskeleton
at the synaptic junction. It lies adjacent to the cytoplasmic face of the
postsynaptic membrane, in close apposition to the active zone of the
synapse and the docked synaptic vesicles in the presynaptic terminal.
Liu et al., 2006. Molecular & Cellular Proteomics 5:1019–1032.
Paired activations of a synapse onto a Layer 2/3 cortical neuron. “Residual Ca2+” in terminal for 10 to 100 msecs after first stimulus increases probability of release.
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, 66-70 (2003)
Long-Term Potentiation in the Hippocampus
The “Tri-synaptic pathway”
Stimulation frequencies that produce LTP usually range from ~50 to 200 Hz.
PTP believed to be caused by a large accumulation of Ca2+ in the terminal caused by a high frequency tetanic stimulation.
Stimulation frequencies usually range from 1 to 10 Hz.
These recordings were made on cultured neurons recorded from with a “whole-cell patch”.
More recently, similar time dependencies have been observed in slices.
From Bi and Poo J. Neurosci. 18, 10464 (1998)
Pre- fires 5-30 msecs before post - LTP
Pre- fires 5-30 msecs after post - LTD
Dual whole-cell patch recordings from neurons in cortical slices from 14-16 day old rats (Markram et al., Science 275, 213 (1997)
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.
NMDA receptors, back-propagating action potentials, and summation of epsp’s appear to be the components that confer “Hebbian” behavior on the synapse.
1. Level and timing of Ca2+ rise in spine determines LTD or LTP.
2. Low frequency synaptic firing (~5 Hz) produces LTD; high frequency synaptic firing (~50 to 100 Hz) produces LTP.
3. The same Ca2+ rules are believed to underlie “spike-timing-dependent synaptic plasticity (STDP).
Detection of intracellular Ca2+ transients with the fluorescent dye, FURA-2
From Grynkiewicz, Poenie, and Tsien (1985) J. Biol. Chem. 260, 3440.
Lisman et al. Nature Rev. Neurosci.3: 175 (2002)
From Schiller, Schiller and Clapham, Nature Neuroscience 1, 114 (1998)
Memory function: 1. calmodulin dissociate after 10 sec of low calcium level; 2. remain active after calmodulin dissociation
Frequency decoder of Calcium oscillation
High frequence, CaM-kinase does not return to basal level before the second wave of activation starts
Accommodation in Hippocampal Neurons
Prolonged stimulation of a neuron produces a burst of action potentials of limited length. Ca2+ influx during AP’s activates dendritic SK channels that cause accommodation, and, when short stimuli are applied, produce a large after-hyperpolarization (ahp).
After application of norepinephrine, the SK channel is inhibited, so that the ahp is smaller and spike trains are longer.
The effect of Norepinephrine is mimicked by agents that increase the level of cAMP.
(then apply glutamate in the presence of TTX)
Simplified diagram of K+ channel familiesfrom Hille, “Ion Channels of Excitable Membranes”
Neurons contain different mixes of channels.
Many of these channels can be modified:
Cardiac Pacemaker - Kir3.4 (among others)
Hippocampal Accommodation - SK1 (among others)
Slow potentials induced by muscarinic receptor - KCNQ’s