Cellular NeurobiologyBIPN140

1st Midterm Exam Ready for PickupBy the elevator on the 3rd Floor of Pacific Hall (waiver)

Exam Depot Window at the north entrance to Pacific Hall (no waiver)Mon-Fri, 10:00 AM to 4:00 PM

1st midterm regrade: contact the IA who graded the question before Nov 14, 2016.

Study Group? If you are interested in studying with other students, please stay after the lecture today.

PS5 Q&A, PS4~7 and Midterm 2 from FA15 are posted.

Chih-Ying’s Office Hour: Monday, 1:00-2:00 PM, Bonner Hall 4146

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.