Synaptic Plasticity and Memory

Transcription

1 Synaptic Plasticity and Memory Properties and synaptic mechanisms underlying the induction of long-term potentiation (LTP) The role of calcium/calmodulin-dependent kinase II (CamKII) in the induction, maintenance, and expression of LTP Current controversies regrading the molecular mechanisms underlying the maintenance of LTP and long-term memories. Stimulate Record Baseline Post-HFS 1

2 LTP induction requires Pre and Postsynaptic Activity Hyperpolarize Postsynaptic Cell during HFS Depolarize Postsynaptic Cell during LFS LTP is Synapse-Specific Pathway 1 Pathway 2 After HFS Before HFS 2

3 LTP is Associative Pathway 2 alone (weak stim) Pathway 2 Pathway 1 and 2 Pathway 1 Pathway 2 Biophysical Properties of NMDA Receptors Explains the Associative Nature of LTP Induction 3

4 Can LTP be Induced by Physiological Realistic Patterns of Synaptic Activity? Hyman et al. J Neurosci 23: 2003 Heurta and Lisman Neuron 15: 1995 Theta-Frequency Presynaptic Stimulation Induces Robust LTP Theta Burst Stimulation 100 Hz } 200 ms (5 Hz) Primed Burst Stimulation 5 mv 200 msec 4

5 Feed-Forward Inhibition is Suppressed during Theta- Frequency Stimulation GABA B Auto-receptor Activation Enables LTP Induction During Theta- Frequency Stimulation 5

6 Postsynaptic Complex-Spike Bursting Enables LTP Induction Grienberger et al., Neuron 81: 2014 Carlisle et al., J Physiol 586: 2008 Theta-Frequency Stimulation Elicits Complex Spike Bursting and LTP Babiec et al., J Neurosci 37:

7 The Role of CS/US Contingency in Associative Learning: How Well Does the CS predict the US? Bauer et al. Nature Neursoci. 4: 687,

8 Bauer et al. Nature Neursoci. 4: 687, 2001 Blocking The Role of Prediction Errors in Associative Learning Rescorla & Wagner Model: V = ( V) V, V change in learning constants related to salience of CS and US asymptote of learning possible associative value of CS (i.e. what s already known) ( -V) = Prediction Error Waelti et al. Nature 412, 2001 Kamin,

9 Adrenergic Receptor Activation Enables LTP Induction Seol et al., Neuron 55: 2007 Novel Exploration Enhances Memory Retention Takeuchi et al., Nature 537:

10 Dopamine Receptor Activation Mediates the Effects of Novelty on Memory Retention Propranolol Adrenergic Blocker SCH23390 D1/D5 blocker Optogenetic Activation of Locus Coeruleus Neurons Enhances Memory Retention 10

11 Optogenetic Activation of Locus Coeruleus Axons Enhances LTP Summary: LTP is an associative form of synaptic plasticity. The biophysical properties of NMDA receptors (i.e. voltagedependent block of channel by extracellular Mg 2+ ) explains associative nature of LTP induction. Mimicking physiological patterns of presynaptic firing provides some of the most powerful protocols for inducing LTP. Pairing presynaptic fiber stimulation with physiological patterns of postsynaptic action potential firing (complex spike bursting) strongly facilitates LTP induction. LTP induction is strongly regulated by modulatory neurotransmitters important for memory formation. 11

12 The Timing Problem. Carlisle et al., J Physiol 586: 2008 Firing Properties of Hippocampal Neurons Place Cell Theta Cell 12

13 Seconds Long Asymmetric Synaptic Plasticity Rule Around Plateau Potential 13

14 Behavioral Time Scale Synaptic Plasticity Behavioral Time Scale Synaptic Plasticity 14

15 Pharmacology of BTSP and Place-Cell Formation Ca2+/Calmodulin-Dependent Kinase II (CamKII) A Calcium-Activated Molecular Switch for Memory 15

16 CamKII Activation Induces an LTP-like Potentiation of Synaptic Transmission Liedo et al., PNAS 92: 1995 LTP Induction Requires CamKII Activity Otmakhov et al., J Neurosci 17:

17 LTP is impaired in CaMKII Mutant Mice Giese et al., Science 279: 1998 NMDA Receptor Activation Triggers CamKII Translocation into Synapses Leonard et al., PNAS 96: 1999 Zhang et al., PNAS 105:

18 Lisman et alnat. Neurosci. 3: 2002 LTP is Impaired in Mice with Knockin Mutations in GluN2B Subunits that Prevent CamKII binding Halt et al. EMBO Journal 31:

19 Reconstitution of a CaMKII Memory Switch Urakubo et al. Biophysical Journal 106: 2014 Phosphorylation and Protein Binding Domains in GluA1 C-terminus 4.1N binding domain MLVALIEFCYKSRSESKRMKGR CLIPQQSINEAIRTSTLPRNSGAG ASGGGGSGENGRVVSQDFPKS MQSIPCMSHSSGMPLGATGL S576 CamKII S816 PKC(?) S818 PKC S831 CamKII (PKC) T840 PKC (CamKII, p70s6k) S845 PKA TGL PDZ domain ligand: (S/T)X(V/L) 19

20 CamKII Activation Enhances AMPA Receptor Channel Conductance GluA1 GluA1+CamKII Ser831Asp ps Barria et al., PNAS 1999 LTP is Abolished in GluR1 Mutant Mice Wild type GluR1 -/- Zamanillo et al, Science 284:

21 GluR1 Phosphorylation at Serine 831 is Increased Following LTP Induction Lee et al., Nature 2000 LTP is disrupted in GluA1 phospho-free mutant mice nissl GluA1 GluA2/3 Lee et al., Cell 112:

22 Changes in Synaptic and Cellular Function Following LTP Induction CamKII Increase conductance of AMPAR channels Trafficking of AMPARs into synapses Increase in dendritic spine size Enhanced intrinsic excitability (modulation of voltage-gated ion channels) Increased in glutamate release from presynaptic terminals (?) New protein synthesis Changes in gene expression 22