BISC 421 1st Edition Lecture 12 Outline of Current LectureI. Synaptc Plastcity II Current LectureSynaptic Plasticity II•What happens in the post synaptic step-‐ how the receptors are changing •Relationship between Ca3 and Ca1 pyramidal neuron • Two Ca3 neurons synapsing onto one Ca1 neuron•If we have a tetanus there is a much larger response – only happens in the Ca1 cell•If we look at the process over tme we get short term and long term responses•The result of the EPSP before and afer the high freq stimulation•Before: just stmulate every few minutes-‐ have steady amplitude•Afer: afer doing high stmulaton and then going back to normal will see this increase in amplitude that will last for a while•Tetanus = high frequency stimulation•This can also happen in long term (days)•Tissue sample that experienced a lot of high frequency stmulaton – lasts a long tme• This is important in learning and memory-‐ hopefully these connectons will stay this wayHow does this happen?•Dependent upon the state of the postsynaptc cell•Need a depolarizaton in the postsynaptc membrane potental in order for this to occur•1. Stmulated at low frequency•2. During this period since they had voltage clamped the membrane they depolarized the membrane while they were stmulatng the neuron then they got the LT•In additon to get LTP it is input specifc – only will happen on the aferent that you are stimulating•Not changing the whole postsynaptc response just the one that we are interested in•Just the relevant ones are changing•Also it is ASSOCIATIVE – if associate with one another can change the other synapse as well. Can change multple synapses as long as they are associatve with each other•What is happening?•Glutamate receptors: AMPA and NMDA receptors•If we release glutamate, bind receptors and actvate•BUT the NMDA receptor only opens if there is depolarizaton (Mg2+ block) – so LTP is dependent upon the depolarizaton of the cell for the NMDA channel to open andhave infux of Ca2+ and Na+•The depolarizaton is dependent upon the AMPA receptor actvation•Need to recruit the NMDA receptors to get an LTP (need depolarizaton and Ca2+ influx-‐second messengerLTP occurs due to increased sensitivity of the postsynaptic cell to glutamate. Ca2+ entry through NMDA receptors produces LTP. Activation of NMDA receptors evokes an increase in intracellular Ca2+. Can be blocked by buffering intracellular Ca2+. Increased Ca2+ starts a phosphorylation cascade. x CamKII and PKC. Final events lead to an increase in the # of AMPA receptors in the post-synaptic terminal.What is Ca2+ doing•Mech of LTP is that now we get increased sensitvity in the post synaptc membrane•Releasing the same amount of NT but getng larger response – why? Because have more receptors•Ca2+ build up in the post synaptc cell which will start a kinase cascade (CamKII and PKC) •Many substrates are phosphorylated (not sure which ones they are) but fnal product is inserton of more AMPA receptors in the post synaptc membrane-‐ causing larger response•Synapses are there but do not respond but afer LTP inducton we can get current-‐ •previously silent but now activeWe are getng insertons of AMPA receptors into the post synaptc membrane that were not there before•If they only have NMDA receptors they will not be actvated but where there is yellow-‐ have both receptors and these will be active•Second graph is afer LTP and frst is before where there was no response•The silent synapses look like the one on the left (only have NMDA receptors)•Afer LTP: inserton of AMP receptors and NOW we can get a response•This is the mechanism – require changes in protein synthesis in order to make it last•If we have inhibitors of protein synthesis-‐ the LTP will not be maintained-‐ NEED the protein synthesis in order for it to be maintained•Can also make brand new synapses-‐ long term changes to the cell•Looking at a CA1 pyramidal neurons•One region of the dendrite afer inducton of LTP we see new spines and shafs coming off –brand new synapsesLTD: another way to form memory is to decrease strength in synapse•Depends on how we stmulate it •Afer stmulaton can see that it is depressed-‐ low frequency over long periods of tmeproduces this•Just get rid of receptors to cause depression•Small slow rise in Ca2+ from long term low freq stmulaton causes LTD•Protein phosphatase actvity (removes phosphates from proteins) causing internalizaton ofAMPA receptors •Just the opposite of LTPThe ability to develop coordinated movements occurs in the cerebellum. Purkinje neurons receive excitatory inputs from two neuron subtypes. Granule cells with parallel fibers. Climbing fibers. A form of associative LTD occurs in the Purkinje neurons when parallel and climbing fbers are activated at the same tme.•Another type of depression in the cerebellum (not hippocampus)•Changes in motor learning•Talking about purkinje cells•Lots of dendritc trees•Depending upon the coordinatng events of two presynaptc cells will lead to depression in purkinje cells•Have parallel fbers that run in parallel through dendritc tree•There are also climbing fbers that weave through the trees•These two fbers depending on how they are stmulated, we can get LTD•This is associatve LTD (pairing of these two fbers stimuli)•Example of another form of associatve response•Looking at response of the parallel fiber•Using metabotropic responses-‐ when we pair stmulaton between these two fbers the climbing fber will actvate the parallel fber increasing Ca2+ increasing PKC which will cause internalizaton of AMPA receptors•By pairing Ca2+ coming from adjacent receptors we can actvate this g protein coupled