BIPN140 Lecture 12: Synaptic Plasticity...
Transcript of BIPN140 Lecture 12: Synaptic Plasticity...
Cellular NeurobiologyBIPN140
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BIPN140 Lecture 12: Synaptic Plasticity (II)
Su (FA16)
1. Early v.s. Late LTP
2. Long-Term Depression
3. Molecular Mechanisms of Long-Term Depression: NMDA-R
dependent
4. Molecular Mechanisms of Long-Term Depression: NMDA-R
independent (cerebellar LTD)
Mechanism II: Ca2+ influx is Required for LTP (Fig. 8.13)
Early phase of LTP (first hour or two)
Dynamic AMPA-R Trafficking During Synaptic Plasticity
Huganir & Nicoll, Neuron 80, 704-717, 2013
Scaffolding and Trafficking Proteins for AMPA-Rs
Huganir & Nicoll, Neuron 80, 704-717, 2013
AMPA-R Phosphorylation and its Trafficking
Song & Huganir, TRENDS in Neuroscience 25, 578-588, 2002
Role of Protein Synthesis in Maintaining LTP (Fig. 8.14)
Mechanisms Responsible for Long-lasting Changes in Synaptic Transmission during LTP (Fig. 8.15)
LTP-induced structural changes
CA1 pyramidal neurons
Synaptic Tagging & Late LTP
Long-term Synaptic Depression in the Hippocampus (Fig. 8.16)Low frequency stimulus (e.g. 1 Hz for 10-15 mins)
Synaptic Efficacy Can Be Regulated Bidirectionally
Dudek & Bear, J Neuroscience 13, 2910-2918, 1993
LFS can eliminate LTP (or induce LTD) as short as 30 minutes after TBS (LTP induction).
Synaptic efficacy can be dynamically tuned up or down (AMPA-R trafficking in and out of synapses).
TBS: Theta burst stimulation, high frequency tetanus to induce LTP
LFS: Low frequency stimulation for 15 minutes to induce LTD.
Spike-timing Dependent Synaptic Plasticity (STDP) (Fig. 8.18)
The precise temporal relationship between activity in the pre- and post-synaptic neurons is also an important determinant of LTP/LTD.
LTPLTD
Action potential superimposed on EPSP
Cerebellar LTD (Fig. 8.17)
(strong excitatory input)
(smaller EPSPs)
Form inhibitory synapses onto cerebellar output neurons (DCN)
Cerebellar LTD: Mechanism
Climbing Fiber
Parallel Fiber
Voltage-Gated Ca2+ ChannelCa2+
AMPA Receptor
mGluR1=> PLC
IP3
DAG
PIP2
PKC
Phosphorylation Internalization LTD
Ca2+
Background: Long-term modification of synaptic strength (LTP & LTD) has long been postulated to encode memory. However, the causal link between LTP/LTD and memory has been difficult to demonstrate.
Experiments: Using fear conditioning (a type of associative memory) as a paradigm to study the impact of optogenetically induced LTP & LTD on fear memory. Expressing channelrhodopsin2 (ChR2, a light-gated non-selective ion channel, optogenetic approach) in the neurons in the auditory cortex that project to amygdala (fear center in the brain). (1) Using light to induce LTD after fear conditioning. (2) Using light to induce LTP subsequently to determine its impact on fear memory.
Results: Optogenetic delivery of LTD conditioning to the auditory input inactivates memory of the foot shock. Conversely, subsequent optogenetic delivery of LTP conditioning to the auditory input reactivates memory of the shock. Thus, the authors engineered inactivation and reactivation of a memory using LTD and LTP, which supports a causal link between these forms of synaptic plasticity and memory.
Fig. 1. Fear conditioning with tone or optogenetics.
1. Animals are trained to press a lever in response to CS (conditioned stimulus, tone or optogenetically driven input, ODI).
2. When animals experience fear, they freeze and stop pressing the lever.
1. Neurons expressing ChR2 respond to blue flashes faithfully with action potential (up to 100 Hz).
2. Provides a means to induce LTD or LTD in vivo in behaving animals.
10 Hz light flashes Lateral amygdala
+40 mV0 mV
-60 mV
US: unconditioned stimulus, foot shock
Fig. 2. LTD inactivates and LTP reactivates memory
(1 Hz x 900 pulses) (100 Hz x 100 pulses x 5)
Fig. 4. In vivo electrophysiological responses to 10 Hz (baseline), LTD and LTP protocols.
Head fixed, anaesthetized animals, extracellular field recording (field EPSP slope)
(optical conditioned stimulus)
Results: Optogenetic delivery of LTD conditioning to the auditory input inactivates memory of the foot shock. Conversely, subsequent optogenetic delivery of LTP conditioning to the auditory input reactivates memory of the shock. Thus, the authors engineered inactivation and reactivation of a memory using LTD and LTP, which supports a causal link between these forms of synaptic plasticity and memory.