Question

You just discovered, for the first time, that LTP causes learning. Describe the molecular changes involved in LTP. The answer should include: how AMPA and NMDA receptors are different, why this matters, how a particular protein kinase is activated, two important ways this protein kinase contributes to LTP, how a particular transcription factor is activated, how the transcription factor contributes to LTP, how retrograde messengers contribute.

Answer 1

LTP stands for LONG TERM POTENTIATION , it refers to long lasting changes which re experience dependent in the efficacy of synaptic transmission. LTP plays key role in learning and memory.

Several experiments are performed to understand the molecular mechanism behind LTP, neural networks are generated continously from sensory input data. It involves 2 features

a)intergrate coding of sensory message or information via neuronal arrays with average firing rate curves, this is quite widespread

b)LTP of synapses between those encoding neurons

Molecular changes involved in LTP

LTP caan be elicited by NMDA RECEPTOR activation (N-methyl D-Aspartate) , belongs to gluatamate receptor type. AMPA and NMDA are ionotropic receptor which are permeable to NA+and K+.

Expression in the early phases are mediated via receptor redistribution(AMPA type receptors redistribute)

For synapse potentiation or weakening, receptors are added or removed , apparent structural changes happen with time along with new protein synthesis.

For induction of LTP both pre and post synaptic neurons should remain active at the same moment, post synpatic neuron should remain depolarised when the release of gluatamate occurs from pre synapse.

simulatenous depolarisation and Glutamate binding, calcium influx occurs leading to activation of signaling cascade which is responsible for synaptic efficacy.

LTP is both input and synapse specific.

NMDA RECEPTOR- non selective cation channel, multisubunit complex, allows entry of Ca+, Na+,K+. EPSP Produced by this causes an increase in calcium amount within post synaptic neurons which act as secondary messanger to drive signaling cascades. They allow entry of cation only when magnesium is not causing a block

AMPA tetrameric, cation permeable ,expressed throughout the brain, , upon gluatamate binding allows opening of pore andsodium influx leading to post synaptic depolarisation , it also allowa ca+influx.

they are enriched at post synaptic membrane(excitatory synapse), their number ranges from few to hundreds, they are dynamic , they show lateral mobility between syanptic and extrasynaptic regions.

Molecular mechanism explaining the kinase are explained in the image attached below,

Induction of LTP in hippocampal neuron(CA3)

NMDA Receptor induced calcium influx trigers signalling casade leading to activation of CaMKII kinase(calcium calmodulin dependent kinase II) phosphorylation of AMPA receptors, receptor trafficking towards synapse, leading to Long term potentiation.

Transcription factors that are involved in LTP includes CREB(cAMP response element binding protein),AP1, Rel/NFKB etc.

The role of kinases and phosphatases in regulating the DNA binding Trancription factors which therfore bind to different gene promoter and activate or repress their transcription.(refer image 3)

please find the reference below

Image A reference Christian Luscher et al., 2012, Cold Spring Harbor Perspectives in Biology ( NMDA RECEPTOR DEPENDENT LONG TERM POTENTIATION AND LONG TERM DEPRESSION)

image b reference Ru Rong Ji et al., 2003, Trends in neurosciences( CENTRAL SENSITISATION AND MEMORY)