10. Nature of plasticity: how plasticity works Flashcards
how does synaptic plasticity produce classical conditioning?
Jirenhead et al (2007)
- in eye blink conditioning the normal spontaneous firing rate of Purkinje cells in relevant areas of the cerebellar cortex is silenced through learning
- before conditioning, CR does not influence the firing of Purkinke cells, which does not change firing rate of cerebellar nuclei
- CS tone does not produce change in Purkinje cell simple spikes implies that the Parallel fibre > Purkinje cell excitatory effect balances the inhibitory effect via inhibitory nuerons (basket and stellate cells)
- during conditioning CS is paired with US (parallel fibre paired with climbing fibre) the synapse (PF>PC) becomes less effective
- if we assume that the inhibitory synapse does not change, Purkinje cells recieve a net inhibitory input when CS comes on
- LTD is how the efficacy of a synapse is reduced
- PC pauses, thereby releasing the firing of the interpositus nucleus
- evidence = Madina and Mauk (2000)
Madina and Mauk (2000)
modelled role of LTD in classical conditioning
- models predict that LTD of synapses between parallel fibres and Purkinje cells produce the conditioned response
is there evidence?
YES = Ito, (1984, 2002) - lots of in vitro work
- electrophysiological recording in slices
- no vibrations, animal movement, blood flow
- stimulate parallel fibres on their own, recording from the cell body of Purkinje cell to get a baseline
- then do manipulation (conditioning) pairing stimulation of parallel fibres and climbing fibres
- then stop climbing fibre stimulation
- PC’s response has now been reduced
- LTD = makes EPSP’s (excitatory post synaptic potentials) smaller (Coesmans et al., 2004)
- clear evidence of LTD in slices
how does the mechanism work?
- parallel fibre > Purkinje cell synapse use glutamate as a neurotransmitter and have 2 kinds of post synaptic receptor:
1. ionotropic receptors
2. monotropic receptors
- when opened by glutamate, ions are allowed in
- these give rise to EPSP’s (and AP’s if strong enough)
- on Purkinje cell, these glutamate receptors are called AMPA receptors - when activated by glutamate, signalling machinery inside the cell is acted on (e.g. release of a second messenger)
- mGluR1 = metabotropic glutamate receptor type 1 (interest)
possible mechanism of LTD
- parallel fibre firing activated both AMPA and mGluR1 receptors
- mGluR1 activation starts a cascade of processes in the cell
- if the climbing fibres also fire, this cascade continues until some AMPA receptors are removed
- removed AMPA receptors reduces the amplitude of EPSP’s induced by parallel fibre stimulation
- but it is more complicated than this a s many cells have complex chemical factors
understanding relevance for conditioning in awake animals
- slices are unatural so we cant assume the processes are the same from that recorded in slices
- LTD observed in slices may not be present in the intact brain
- lead to hypotheses but need experiments to test link between biochemistry to behaviour
- knock out mice = bread mutant mice that lack LTD in slices but show normal eye blink conditioning (Schonewille et al (2011)) - puzzling…
if the mutant mice lack LTD in slices but still show normal eye blink conditioning, whats responsible?
2 possibilities:
- just not as simple
- type of stimulation
possibility 1
Johansson et al (2015) - just not as sikple as we originally thought - idea of new kind of plasticity
- decerebrate ferret (half way between slice and awake animal)
- CS = electrical stimulation of the forelimb
- US = electrical stimulation of CF (burst)
- recorded from Purkinje cell
- before training there is no effect of CS
- after training, we see a pause in simple spike firing in Purkinje cells (originally shown in Jirenhead et al., 2007)
- pause still present if mGluR1 receptor blocked/AMPA as well - fits knock out mice
- pause disappears if you block the mGluR7 receptor
- AMPA receptors not involved
mGluR7
- appears to act on a protein that activated a potassium channel, reducing the chance of EPSP’s as it inhibits the Purkinje cell
- plausible as works on similar things
- done recently so no time for repetition as its v complex method
possibility 2
Yamaguchi et al (2016) - LTD can be obtained in the knock out mice if the induction procedure is changed
- if you change the stimulation type you get LTD
- if you have paired parallel fibre stimulation (with second stimulation paired with CF) the mutant mice produce LTD
but what is the underlying mechanism?
need more research as we dont understand as much as we once thought. no solid evidence for the mechanism underlying LTD
