I. Hebb synapse. Learning is modification of synapse.
 A. Synapse strengthened if presynaptic and postsynaptic cell are active simultaneously.
 B.    cells that fire together, wire together
 C. If two inputs occur together, the response to their simultanous activation increases.
 D.  repeated activation also increases postsynaptic response.
II. What properties of synapses might change?
 A. change in transmitter release
 B. change in post synaptic receptors
 C. change in number of synapses
 D. change in shape of synapse, e.g. dendritic spines, number of spines
III. LTP is long term potentiation; lasts days in some situations.
IV. synaptic organization in preparation used to study LTP
 A. CA1 cells get input from Schaeffer collateral fibers (axons of CA3 cells) as well as other places.
 B. CA1 axons provide outputs from hippocampus
 C. In type of LTP considered here, one stimulates Schaeffer collaterals and record from CA1 cells.
V. how to record LTP
 A. put recording electrode near cells that you want to be potentiated. Can record intra or extracellularly.
 B. stimulate Schaeffer collateral and record in CA1.
 C. If recording intracellularly, measure epsp before and after tetanus.  Measure slope rather than amplitude.
 D. tetanize Schaeffer collaterals for 1 sec at 100/sec, do this twice. This stimulus will cause action potentials in the Schaffer collaterals.  These action potentials will release glutamate onto the CA1 cells and depolarize them.
 E. now measure epsp in response to a single stimulus.  It will be larger. It will remain larger for several hours.
 F. can also obtain LTP in living rabbits, so not just artificial phenomenon. LTP can last several days in intact animal.
VI. Mechanism of LTP induction in CA1.
 A. glutamate is the transmitter.  Activates several types of receptors: NMDA and non NMDA.
 B. a single input does not permit NMDA channels to open because these channels are blocked by Mg2+.
 C. the opening of NMDA channels requires both depolarization and release of transmitter from presynaptic endings.
  1. Initially the tetanus depolarizes the cell.
  2. This allows Mg2+ to leave so that channel is no longer blocked.
  3. Now glutamate can open the channel.
 D. Ca2+ enters through NMDA channels (along with some Na+).
 E. This activates Ca2+ dependent enzymes that cause permanent changes in cell.
 F. When single stimulus later activates non-NMDA channels, it causes a potentiated response.
VII. Induction is postsynaptic in CA1
 A. hyperpolarization of postsynaptic cell during tetanus prevents LTP.
 B. prevented by drugs that increase inhibition.
 C.  intracellular depolarization produces LTP (Gufstafson)
VIII.  NMDA receptors
 A.  require glutamate and depolarization.
 B. Mg2+ block relieved by depolarization
 C. Ca++ enters
IX. evidence that activation of NMDA receptors is required for induction LTP
 A. prevented by blockade of NMDA receptors (fig). not by blockade of AMPA receptors.
 B. decreased Mg2+ in extracellular fluid increases ease of obtaining LTP
X. Maintenance of LTP may be presynaptic.  If so, it would require communication between presynaptic and postsynaptic membrane.  APV does not damage maintenance.
XI.What is the mechanism.  Turns out that activation of NMDA receptors results in an increase in AMPA receptors.
 A. first step is Ca++ entry
 B. This activates several enzymes\
 C. result of enzyme activation is phosphorylation of CREB
 D.  CREB goes to nucleus and activates IEGs
 E.these cause synthesis of proteins that go back to nucleus and activate other genes.
 F. of the genes activated is responsible for synthesis of AMPA receptors.
 G. AMPA receptor gene inserted into virus permits you to see increase in AMPA receptors.
XII. behavioral concomitants: Animal experiments suggest hippocampus is involved in finding one's way in space. Does activation of hippocampal cells when animal is doing a spatial learning task resemble LTP?  If so, it should be dependent on NMDA receptors.
 A. milk maze. animal is supposed to find platform in murky water.   Takes much longer to do so when injected with APV. Dose of APV is about same as dose of APV required to prevent LTP.
 B. APV does not decrease performance when animal can see platform.
 C. radial arm maze: rat is supposed to go to each arm once for food.  learns to do this much more slowly if has hippocampal lesion or APV treatment.
 D.Mutants that lack the NR1 subunit of the NMDA receptor in the CA1 region of
            the hippocampus also have normal synaptic transmission but  do not have LTP and have a deficit in learning the milk maze.