1. NEUROBIOKIMIA: ASPEK BIOMOLEKULER DARI MEMORI Oleh Mohammad hanafi

2. 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

3. 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.

4. Molecular mechanism Short-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 Ca 2+ influx through voltage sensitive Ca 2+ - channel  Serotonin  GoR  activate phospholipase C (PLC)  formation DAG  activate PKC  PKA & PKC  phosphorylate L-type Ca 2+ channel  open the channel

5.  The net effect ↑ flow in Ca 2+ 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

7. 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

8. 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

10. 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)

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

12. Single train Stimulation  act nNOS  retrograte Factor  ↑ Glu release

13. 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

19. 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