. Neurobiology, lecture on Synapse Formation

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Neurobiology

text:
Principles of Neural Science

- Kandel, Schwartz and Jessell:
Read pages 1087-1113 for this lecture

end

 XIV. Synapse Formation			back to XIII. Synapses


	A. Synapse formation establishes neuronal connection and is important for the
	    survival of the presynaptic neuron


		1. if the axon does not reach its target the neuron often dies


			a. lots of cells die during development


	B. Survival of Neurons is regulated by interactions with other neurons


		1. an excess of  neurons is generated initially


			a. neuronal cell death occurs normally during development, so that
			   the surviving neurons match the size of the functional objective


				i. i.e. more neurons survive to innervate a large structure
				   (such as a limb) than a small structure


		2. the number of neurons remaining is an effect of the target tissue on
		   the  differentiation and maintanence of neuroblasts and neurons


			a. neuronal death increases when the target is removed


	C. Growth and Neurotrophic Factors


		1. Nerve Growth Factor


			a. sensory, sympathetic, and some central neurons depend on NGF for
			   their survival


				i. giving NGF to embryos prevents naturally occuring neuronal death


				ii. NGF is produced by the targets of the neurons


				iii. [NGF] determines the density of innervation


			b. [NGF] is very low


				i. peripheral axons compete for a limited supply of trophic factor


			c. 130,000 mw, 3 subunit protein (a, b, g)


				i. encoded for by 3 genes


				ii. b-subunit contains the active component


			d. 2 subunit membrane receptor


				i. in a family of receptors (similar proteins) that bind other
				   neurotrophic factors
		
		
					(1) binds to b-subunit
					
					
					(2) triggers various 2nd messenger pathways
					    like MAP K


			e. NGF-receptor complex is taken up by nerve terminals


				i. retrograde transport to the cell body


					(1) blocking transport causes cell death


			f. mature neurons remain sensitive to NGF


				i. increases synthesis of enzymes and transmitters


		2. many neurons dependent on targets for survival are not supported by NGF


			a. e.g. parasympathetic neurons and spinal motor neurons


		3. Brain-derived neurotrophic factor and Neurotrophin 3 (N3)


			a. derived from the same multi-gene family as NGF


				i. very similar structurally to NGF


			b. support sensory neurons, and dorsal root ganglion and
			   proprioceptive neurons respectively


		4. Ciliary neuronotrophic factor (CNTF)
	
	
			a. supports parasympathetic ciliary ganglion neurons


		5. muscles produce neurotrophic factors


			a. muscular activity can determine the survival of motor neurons


				i. decreased muscular action increases innervation


			b. may be similar to CNTF


			c. some synapses are eliminated during development


				i. most muscle fibers in adults are connected to a single motor axon


				ii. function depends on precise regulation of the number of
				    motor nerve terminals


			d. innervation changes the contractile properties of the muscle


				i. neurons that innervate fast-twitch have rapid conduction
				    velocity and brief hyperpolarization


				ii. the neuron determines whether it will be a fast or slow
				    twitch muscle fiber


		6. Epidermal Growth Factors (EGF), Fibroblast Growth Factors (FGF), and
		   Interleukins (especially IL1) are also neurotrophic factors


		7. Neurotrophic factors also repair damage to neurons, retard degeneration,
		   stimulate axonal and dedrtic sprouting (neurite outgrowth) and
		   differentiation of neurons


		8. some neurotrophic factors stimulate synthesis of others


			a. IL1 stimulates NGF


			b. NGF induces its own receptors
			
		
		9. Neurotrophin Receptor Family 
		
		
			a. many contain intrinsic kinase activity
			   = TrK (tyrosine kinase) or JaK (Janus Kinase)
			
			
				i. NGF and N6 bind to TrKA
			
			
				ii. BDNF and N4 bind TrKB
			
			
				iii. N3 binds to TrKC
				
				
				iv. there are also non-kinase forms
				
				
	D. Neurotrophin Receptor 2nd messenger systems
	

		1. MAP Kinase
	
	
			a. ligand binding phosphorylates receptor: tyrosine PK
		
		
			b. phosphorylated receptor activates GRB2
		                   (Growth factor Receptor Bound protein)
		
		
			c. GRB2 activates Sos (conformational change)
		
		
				i. Sos is the protein product of the Sos gene
		
		
			d. Sos binding Ras allows GTP phosphorylation of Ras
		
		
				i. Ras is a G protein from the Ras gene
			
			
					(1) GAP protein stimulates Ras GTPase
				                          (GTPase Activation Protein)
		
			e. Ras activates Raf1 (conformational change
		                 and becomes associated with membrane)
		
		
			f. Raf1 is a kinase and phosphorylates MAP KK (also MEK)
		

				i. MAP KK is a dual specificity Kinase
			
			
					(1) may also be activated by PKC or Gbg
		
			g. MAP KK phosphorylates MAP Kinase
		   	    (Mitogen Activation Proteins)
		
			h. MAP K phosphorylates transcription factors ®
		             ® translocate to nucleus
		
		
			i. receptors that ­ MAP K:
		
		
				i. NGF-R, EGF-R, PDGF-R, NT-R


		2. Akt 
	   
	   	
			a. Neurotrophins via Akt promotes Cell Survival/block cell death


			b. Akt is in a family of protein kinases related to PKA and PKC


				i. Akt is aka PKB, Akt1,
				 & RAC-PK (PK - related to A & C)

				
				ii. Akt2, Akt3


			c. neurotrophin binding ® PI3-K (phosphoinositide 3 Kinase)


				i. PI3-K ® Akt
			
			
					(1) translocaton of Akt to membrane necesary
				
				
				ii. PDK1 (phosphoinositide-dependent kinase 1)
			                    necessary for both phosphorylations
			
			
			d. Akt activates systems that prevent cell death
		
		
				i. after osmotic or oxidative stress,
			               or withdrawl of neurotrophins
			   
			   
			   		(1) protects from irradiation or chemotherapy
				
				
					(2) but also plays an important role in cancer
				
				
						(a) cell survival under conditions 
						    that would normally cause elimination
							
							
				ii. by phosphorylating and thereby inhibiting
			                     forkhead transcription factors
			
			
					(1) FhTF ® Fas ® apoptosis		
			


			
	E. Proper Neuronal Function


		1. depends upon synaptic connections with appropriate targets


			a. axon of a developing neuron must make contact with postsynaptic cell


			b. contacts between growth cone and target must be stabilized


				i. assembly of specialized structures
				    that permit transmitter release


				ii. specialized structures for reception on postsynaptic cell


	F. Synapses Learning and Memory


		1. Learned information may be stored as short-term or long-term memory


			a. short-term memory does not require protein synthesis


				i. extant enzymes facilitate potentiation (LTP)
				    of synaptic transmission


					(1) via NMDA receptors


						(a) facilitated by other transmitters or
						      neurotrophins 
						     like: NO, BDNF, CRF, DA, NE, 5-HT, ACh


		2. Long-term memory requires protein synthesis and new synapse formation


			a. repetitive learning tasks enhance this synaptogenesis


				i. ubung macht den miester, practice makes new synapses


			b. LTP may enhance transmission in these new synapses


		3. synapses may be lost when repetitive stimulation is removed

XV. Synapse Connection and Circuit Development



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University of South
		Dakota......Department of Biology