NEUROBIOKIMIA:ASPEK BIOMOLEKULER

DARI MEMORI

OlehMohammad hanafi

Learning and memory

• Learning : the process by which we acquire new knowledge.

• Memory : the process we retain that knowledge• In Aplysia, simple reflex could be modified by three

different form of learning : habituation, sensitization, and conditioning.

• ER Kandel first concentrate in sensitization.• Simple reflex is simple learning implicit learning

acquire implicit memory (non-declarative memory = procedural memory)

• Theory on memory storage : 1.in the growth of new connection. 2.self-reexciting chain of neuron

Implicit learning and memory

• ER Kandel (from 1957 – still in progress) searching the molecular basic of memory storage.

• In Aplysia, sensitization: a form of fear where by an aversive shock to the tail, recognized the stimulus as aversive and learns to enhance its defensive reflex responses to a variety of subsequent stimulus applied to the siphon, even innocuous stimulus.

• A single shock gives rise to a memory last only minutes (short-term memory)

• Four to five spaced shock to the tail a memory lasting several days (long-term memory)

• Short-term memory does not require synthesis of new protein, but long-term memory, it does require.

Molecular mechanismShort-term sensitization Stimulation of sensory neuron in the tail activates

specific interneuron that facilitate sensitization. Form contacts with axon of sensory neuron

Serotonin released by facilitating neuron bind to two types of G protein resceptors of ssensory axons.

Serotonin GsR ↑ cAMP ↑ PKA phosphorylate K+ channel inactivate the hyperpolarizing K+ channel (1) prolong action potential (2) ↑ duration of Ca2+ influx through voltage sensitive Ca2+-channel

Serotonin GoR activate phospholipase C (PLC) formation DAG activate PKC

PKA & PKC phosphorylate L-type Ca2+ channel open the channel

The net effect ↑flow in Ca2+ into the axon

↑ transmitter release ↑ gill withdrawal Long-term sensitization Repeated stimulation ↑ level cAMP ↑PKA recruits

Mitogen-activated protein kinase (MAP) PKA & MAP translocate to the nucleus PKA phosphorylate & activate the transcription factor

CREB1 (cAMP-response element-binding protein) activates immediate-response genes for synthesis proteins ( 1. Ubiquitin hydrolase PKA persistent activity. 2. C/EBP (CAAT Enhancer Binding Protein = transcription factor activate genes for synthesis protein growth new synaptic connection

Explicit learning and memory

• Require conscious recall and concern with memory for people, place, and event. Involve the medial temporal lobe and structure deep to it hippocampus.

• Hippocampus contain a cognitive map of space, lesion to it interfere with spatial task.

• Within hippocampus the Perforant pathway, Schaffer (Sch) collateral pathway, and Mossy fiber pathway

• Stimulation of CA3 Sch collateral and recoded in CA1 – LTP (long-term potentiation)

• LTP : 1.fundamental property of the majority of exitory synapses in the mammallian brain

2.synaptic change that may underlie learning and memory

• Early phase LTP is elicited with a single train of stimuli is given for one second at 100 Hz. Lasts 2 – 3 hours

• Late phase LTP after four trains stimuli separated by 10 minuts. Lasts >= 24 hours

• LTP : -occur in many parts of the brain due to increased synaptic efficiency -it function probably not only related to memory synapse specific -restricted to synapse that has been repeatedly used -comprised in two phases;

a.short induction phase (short-term memory) b.late expression phase (long-term memory

Molecular mechanism of LTP• Stimulation (1)↑ dependent exocytosis of glutamate

presynaptic neuron, post synapticly :

(2) ↑ activation of AMPAR

(3) ↑ depolarization relieves Mg blockage of

NMDAR ↑ Ca entry (4) activate mGlutR (=metabotropioc)

phosphorylation of NMDAR further ↑ Ca entry (5) high entry Ca trigger Ca /calmodulin dependent Kinase, CK, PKC, and Fyn together induces LTP (short-term explicit memory storage)

Calcineurin : endogenous Ca2+- sensitive phosphatase inhibitory costrain on expicit memory

Single train Stimulation actnNOS retrograteFactor ↑ Glu release

Late phase LTP

Repeated stimulation ↑ level cAMP ↑PKA recruits Mitogen-activated protein kinase (MAPK)

PKA & MAPK translocate to the nucleus PKA phosphorylate & activate the transcription

factor CREB1 (cAMP-response element-binding protein) activates effector for growth (tPA,BDNF) and regulator (C/EBPβ (CAAT Enhancer Binding Protein β) synthesis protein growth new synaptic connection

Conclusion

• Memory storage involves in the synaptic changes

• Short-term memory storage (SMS) covalent modification of preexisting protein (no new protein synthesis) ↑ synaptic strength

• Long-term memory storage protein synthesis

new synaptic connection• SMS implicit serotonin; explicit glutamate• LMS : implicit = explicit PKA, MAPK, CREB-1