8/30/16'1'Glial'cell'biology'&'neuron/glia'interac7ons'Cellular'Neurobiology'1'September'2016'Kelly'Monk'email:'[email protected]'website:'hHp://monklab.wustl.edu'(Cajal,'1905)'(Livet…Sanes,'Lichtman,'2007)'The'neuron'is'the'basic'func7onal'unit'of'the'nervous'system'Some'examples'of'CNS'glia:'Some'examples'of'PNS'glia:'(Allen'and'Barres,'2009)'' (Corfas'et'al.,'2004)''Yet,'glia'(can)'outnumber'neurons'10:1'in'the'human'brain''8/30/16'2'Neurons'vs.'glia'• The'defining'characteris7c'of'a'neuron'is'its'ability'to'transmit'rapid'electrical'signals'in'the'form'of'ac7on'poten7als.'• All'other'neural'cells'that'lack'this'property'are'broadly'called'glia.'– Tradi7onally,'glia'have'been'viewed'as'passive'cells'that'help'to'maintain'the'func7on'of'neurons.'Overview'• Nervous'system'development'• Brief'history'of'glia'• Central'nervous'system'glia'– astrocytes)– oligodendrocytes)– microglia'– ependymal'cells'– radial'glia'• Peripheral'nervous'system'glia'– myelina0ng)Schwann)cells)– non-myelina7ng'Schwann'cells'– boundary'cap'cells'– olfactory'ensheathing'glia'– satellite'cells'Vertebrate'nervous'system'development'-Animals'with'bilateral'symmetry'have'three'germ'layers:'endoderm,'mesoderm,'ectoderm'-The'en7re'nervous'system'arises'from'the''ectoderm'(except'for'microglia)'8/30/16'3'Vertebrate'nervous'system'development'-Animals'with'bilateral'symmetry'have'three'germ'layers'-The'en7re'nervous'system'arises'from'the''ectoderm'(except'for'microglia)'-A'por7on'of'the'dorsal'ectoderm'is'specified'to''become'the'neural'ectoderm.'(Gilbert,'Developmental'Biology,'9th'Edi7on)'Brief'history'of'glia'• Virchow'generally'credited'with'the'discovery'of'CNS'glia'(1856,'1858).'• Was'actually'arguing'that'there'is'a'connec7ve'substance'in'the'brain,'nervenki','or'neuroglia.'(Virchow,'1858)'Brief'history'of'glia'• Deiters'(1865)'first'iden7fied'non-neuronal'cells'in'the'CNS'as'cells'that'lack'axons.'• Schwann'(1839)'realized'that'the'“white'substance'of'nervous'fibers”'was'associated'with'individual'cells'and'iden7fied'Schwann'cells'in'the'PNS.'(Deiters,'1865)'(Schwann,'1839)'8/30/16'4'Brief'history'of'glia'• By'1920,'major'classes'of'CNS'glia'had'been'inden7fied.'(Cajal,'1913)'(Del'Rio-Hortega,'1920)'CNS'glia'• Astrocytes'and'Oligodendrocytes'Development'of'astrocytes'and'oligodendrocytes'• All'neurons'and'glia'(except'microglia)'in'the'developing'CNS'develop'from'precursor'cells'derived'from'the'neuroectoderm.'8/30/16'5'Development'of'astrocytes'and'oligodendrocytes'(Rowitch'and'Kriegstein,'2010)'Development'of'astrocytes'and'oligodendrocytes'(Rowitch'and'Kriegstein,'2010)'Development'of'astrocytes'and'oligodendrocytes'(Rowitch'and'Kriegstein,'2010)'8/30/16'6'Development'of'astrocytes'and'oligodendrocytes'(and'neurons,'radial'glia,'and'ependymal'cells)'(Rowitch'and'Kriegstein,'2010)'Astrocytes'(Allen'and'Barres,'2009)''Astrocyte-astrocyte'communica7on'• Astrocytes'communicate'with'one'another'through'waves'of'calcium'ions.'• Can'propagate'informa7on'over'large'distances.'• S7mula7on'of'one'astrocyte'can'cause'a'calcium'response'in'a'subset'of'neighboring'astrocytes,'but'not'others,'sugges7ng'dis7nct'networks'of'astrocytes.'• Low'level,'constant'communica7on'may'also'occur.'calcium'indicator' astrocyte'marker'(Nimmerjahn'et'al.'2004)'8/30/16'7'Astrocyte-astrocyte'communica7on'• Astrocytes'communicate'with'one'another'through'waves'of'calcium'ions.'(Kuga'et'al.,'2011)'Astrocyte-astrocyte'communica7on'• Individual'astrocytes'occupy'dis7nct'domains.'• Cellular'projec7ons'from'neighboring'astrocytes'do'not'overlap'in'the'normal'adult'brain.'• Cells'are'linked'together'by'gap'junc7ons'(Spacek,'2000)'(Sofroniew,'2009)'Func7ons'of'Astrocytes'• Contribute'to'brain'homeostatsis.'• Act'as'physical'barriers'between'the'synap7c'connec7ons'of'neighboring'neurons.'• Modulate'neurotransmission.'• Modulate'synapse'forma7on/synapse'number'– promo7ng'synaptogenesis'– removing'synapses'by'phagocytosis'8/30/16'8'Astrocytes'and'brain'homeostasis'–'regula7on'of'blood'flow'• Numerous'fine'processes'of'astrocytes'form'close'associa7ons'with'capillaries'and'neurons.'• Enhanced'neuronal'ac7vity'causes'astrocytes'to'signal'to'blood'vessels'for'regional'increases'in'blood'flow.'• Results'in'enhanced'delivery'of'oxygen'and'glucose'to'the'ac7ve'brain'regions.'Astrocytes'and'brain'homeostasis'–'lactate'shuHle'• Besides'regula7ng'blood'flow,'astrocytes'transport'glucose'and'oxygen'from'blood'to'neurons.'• It'is'hypothesized'that'astrocytes'convert'glucose'into'lactate.'• In'this'model,'lactate'is'exported'to'neurons,'and'converted'to'pyruvate'to'produce'ATP.'(Pellerin'et'al.'1998)'Astrocytes'and'brain'homeostasis'–'the'tripar7te'synapse'• Individual'astrocytes'can'make'contact'with'and'ensheath'100s-1000s'of'synapses.'• Astrocytes'possess'many'of'the'same'neurotransmiHer'receptors'as'neurons.'• NeurotransmiHer'release'by'neurons'ac7vates'calcium-based'signaling'cascades'in'astrocytes.'• Astrocytes'then'release'neuroac7ve'substances'back'to'neurons'to'be'used'to'make'more'neurotransmiHers.'• Also'maintain'appropriate'ion'concentra7on'of'extracellular'fluid'surrounding'neurons'by'taking'up'excess'potassium'(Eroglu'and'Barres,'2010)'8/30/16'9'The'tripar7te'synapse?'• In'vitro,'glutamate'can'evoke'rises'in'intracellular'Ca2+'in'cultured'astrocytes,'which'can'evoke'a'Ca2+'response'in'adjacent'neurons.'• However,'most'studies'performed'in(vitro'and'issues'regarding'promoter'specificity'for'in(vivo(studies'have'not'been'resolved.'(Smith,'2010)'Astrocyte-neuron'interac7ons'(Freeman,'2010)'Astrocyte-neuron'interac7ons'• Purified're7nal'ganglion'cells'(RGCs)'survive'in'culture,'but'show'liHle'spontaneous'synapse'ac7vity'and'form'few'synapses'(Eroglu'and'Barres,'2009)'8/30/16'10'Astrocyte-neuron'interac7ons'• RGS'cultured'in'the'presence'of'a'feeding'layer'of'astrocytes'or'astocyte-condi7oned'medium'show'~10-fold'more'excitatory'synapse'ac7vity'and'5-7-fold'increase'in'the'number'of'synapses.'Astrocyte-neuron'interac7ons'• There'are'at'least'three'classes'of'astrocyte'synapse'factors:'– factors'that'induce'structurally'normal'but'postsynap7cally'silent'synapses.'–
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