LTP

1. LTP

2. Overview • LTP as candidate mechanism for (Hebbian) learning in the brain at the level of neurons • Hippocampus overview • LTP, an introduction • LTP mechanisms • LTP studies (proof of LTP mechanisms)

3. Learning • Where does learning take place at the neuronal level? What do we mean when we say neurons are plastic? • Neurons are plastic at the synapses. • Change in synaptic connectivity might constitute the mechanism of learning

4. Hebbian Learning • "when an axon of cell A ... excite a 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, 1949) • Cells that fire together, wire together

5. Hebbian Learning, Continued A B C Pre-Synaptic Neuron Axon “Hebbian” learning Synaptic Cleft Dendrite Post-Synaptic Neuron

6. Mechanism for Hebbian Learning • LTP is a candidate mechanism for Hebbian learning (synaptic plasticity) • LTP is a persistent increase in synaptic strength (as measured by the amplitude of the EPSP) that can be rapidly induced by brief neural activity

7. Where does LTP occur • LTP has been found in mammalian neocortical regions, and in subcortical nuclei • LTP has also been found in the peripheral nervous system of mammals • LTP has mainly been studied in the hippocampus, a vital structure for memory

8. Location of Hippocampus

9. Parasagital view of Brain Including Hippocampus

10. Horizontal Slice

11. Histological Section of Hippocampus Legend EC = Entorhinal Cortex S = Subiculum DG = Dentate Gyrus CA3 = CA3 field CA1 = CA1 field (PrS = PreSubiculum) (PaS = ParaSubiculum)

12. Hippocampal Connectivity

14. Neurogenesis, An Aside • The dentate gyrus continuously creates new neurons! • New neurons necessary for learning across time delays (Shors et al, 2001) • New neurons necessary for generating random context which minimizes interference, creates distinct codes (Becker, 2005)

15. Original LTP Study • By Timothy Bliss and Terje Lomo (1973) • Done on an anaesthetized rabbit’s hippocampus • Brief, high-frequency stimulation of the perforant pathway input to the dentate gyrus produced a long lasting enhancement of the extracellular recorded field potential

16. General LTP Experimental Design Stimulation of a bundle of presynaptic axons Recording of monosynaptic EPSP

17. Typical Results Typical Results

18. LTP Recording Techniques • In Vivo – in live animals • In Vitro – slice preparations, taken out of animal and manipulated in lab • Extracellular recording – multiple neurons • Intracellular recording – single neuron

19. Properties of LTP • Rapid • Long Lasting effects • Specificity • Co-operative • Associative

20. How Does LTP Work? • LTP requires some sort of additive effect • High-frequency stimulation • Activation of synapses and depolarization of the postsynaptic neuron must occur at the same time • LTP additive effect takes place due to workings of glutamate receptors

21. Glutamate • Glutamate is an excitatory neurotransmitter in CA1 • There are two kinds of glutamate receptors: AMPA and NMDA • AMPA receptors are simple – the presence of glutamate opens channels for sodium (Na+) ions.

22. NMDA • Mg2+ blocks ion channel • When cell is depolarized, Mg2+ forced away • Ca2+, as well as Na+, can enter through ion channels

23. AMPA (Post-Synaptic)

24. NMDA

25. Long-Term Changes