2. Long term potentiation (LTP) of an excitatory synaptic inputs is input specific

3. Weak stimulation Strong stimulation tetanus LTP shows cooperativity between excitatory synaptic inputs

4. LTP is associative

5. Cooperativity This term refers to the fact that when using high frequency stimulation to induce LTP, a crucial number of presynaptic fibres must be simultaneously activated — they must 'cooperate' to elicit LTP (that is, a threshold stimulation strength must be used). The frequency of stimulation interacts with the stimulus strength such that increasing one decreases the requirement for the other to trigger LTP. This property is explained by the fact that, to trigger LTP, the postsynaptic cell must be sufficiently depolarized to allow current (particularly Ca2+) to flow through the NMDA receptor channel. Input (synapse) specificity This property refers to the fact that, when LTP is elicited at one set of synapses on a postsynaptic cell, adjacent synapses that were not activated during the induction protocol do not show LTP. This property is explained by the requirement that, to elicit LTP, synaptic NMDA receptors must be activated, leading to a spatially restricted increase in intracellular Ca2+ in the relevant dendritic spine. Associativity This term refers to the fact that LTP can be elicited at synapses that are activated by low-frequency, sub-threshold stimuli if their activation is temporally concurrent with an LTP-inducing stimulus at another set of synapses on the same cell. This property is explained by the fact that the LTP-inducing stimulus provides the requisite depolarization, which is rapidly transmitted through the dendritic tree to those synapses in which the NMDA receptors were simultaneously activated by the sub-threshold stimulus. It is easy to envision how this property makes LTP an attractive mechanism for associating two pieces of information being conveyed by different sets of afferents that synapse on the same postsynaptic cell. Malenka Nat. Rev. Neurosci. 4, 923 (2003)

6. Hyperpolarization of a neuron during tetanic stimulation prevents the induction of LTP HFS: High frequency (tetanic) stimulation LTP Induction Mechanism

7. Pairing protocol: Depolarization of the cell with current injection together with stimulation of input 1. (Note that input 2 was stimulated only at times when no current was being injected into the cell.) Wigstrom et al 1986 Repetitive depolarization of a neuron in conjunction with synaptic stimulation (pairing) is sufficient to induce LTP { LTP Induction Mechanism Pairing

8. APV Time (min) EPSP (% of baseline) APV Block of LTP Tetanus LTP Induction Mechanism APV is a competitive antagonist of NMDARs

9. Gly Glu ++++++++ -------- ------ ++++++ Synaptic Glutamate Alone Cytoplasm Synaptic Cleft Mg ++ Ca ++ Glu Ca ++ ++++++++ -------- Mg ++ Gly ------ ++++++ Glutamate plus Membrane Depolarization CytoplasmSynaptic Cleft Ca ++ Coincidence Detection by the NMDA Receptor Na + K + Na + K + LTP Induction Mechanism

10. Ca 2+ influx is necessary Perfusion of the postsynaptic neuron with the Ca 2+ buffer EGTA blocks LTP LTP Induction Mechanism

11. Visualization of Ca2+ influx through synaptically activated NMDARs