title: Astrocyte-derived thrombospondins mediate the development of hippocampal presynaptic plasticity in vitro.
abstract: Astrocytes contribute to many neuronal functions, including synaptogenesis, but their role in the development of synaptic plasticity remains unclear. Presynaptic muting of hippocampal glutamatergic terminals defends against excitotoxicity. Here we studied the role of astrocytes in the development of presynaptic muting at glutamatergic synapses in rat hippocampal neurons. We found that astrocytes were critical for the development of depolarization-dependent and G(i/o)-dependent presynaptic muting. The ability of cAMP analogues to modulate presynaptic function was also impaired by astrocyte deficiency. Although astrocyte deprivation resulted in postsynaptic glutamate receptor deficits, this effect appeared independent of astrocytes' role in presynaptic muting. Muting was restored with chronic, but not acute, treatment with astrocyte-conditioned medium, indicating that a soluble factor is permissive for muting. Astrocyte-derived thrombospondins (TSPs) are likely responsible because TSP1 mimicked the effect of conditioned medium, and gabapentin, a high-affinity antagonist of TSP binding to the α2δ-1 calcium channel subunit, mimicked astrocyte deprivation. We found evidence that protein kinase A activity is abnormal in astrocyte-deprived neurons but restored by TSP1, so protein kinase A dysfunction may provide a mechanism by which muting is disrupted during astrocyte deficiency. In summary our results suggest an important role for astrocyte-derived TSPs, acting through α2δ-1, in maturation of a potentially important form of presynaptic plasticity.
authors.affiliation: Graduate Program in Neuroscience, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
authors.forename: Devon C
authors.initials: DC
authors.lastname: Crawford
authors.forename: Xiaoping
authors.initials: X
authors.lastname: Jiang
authors.forename: Amanda
authors.initials: A
authors.lastname: Taylor
authors.forename: Steven
authors.initials: S
authors.lastname: Mennerick
mesh_terms: D000241:Adenosine / Q000031:analogs & derivatives / Q000494:pharmacology; D000588:Amines / Q000494:pharmacology; D000818:Animals; D000831:Animals, Newborn; D001253:Astrocytes / Q000502:physiology*; D001703:Biophysics; D050882:CREB-Binding Protein / Q000378:metabolism; D018920:Coculture Techniques; D017077:Culture Media, Conditioned / Q000737:chemistry / Q000494:pharmacology; D000242:Cyclic AMP / Q000031:analogs & derivatives / Q000494:pharmacology; D003509:Cyclohexanecarboxylic Acids / Q000494:pharmacology; D034284:Dynamin I / Q000378:metabolism; D004558:Electric Stimulation; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects; D005260:Female; D000077206:Gabapentin; D006624:Hippocampus / Q000166:cytology* / Q000254:growth & development*; D008297:Male; D016202:N-Methylaspartate / Q000494:pharmacology; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009473:Neuronal Plasticity / Q000187:drug effects*; D009924:Organ Culture Techniques; D018408:Patch-Clamp Techniques; D010766:Phosphorylation / Q000187:drug effects; D011189:Potassium Chloride / Q000494:pharmacology; D017729:Presynaptic Terminals / Q000187:drug effects*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011810:Quinoxalines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D018091:Receptors, AMPA / Q000378:metabolism; D018709:Statistics, Nonparametric; D013569:Synapses / Q000187:drug effects; D013873:Thionucleotides / Q000494:pharmacology; D019699:Thrombospondins / Q000378:metabolism / Q000494:pharmacology*; D014633:Valine / Q000031:analogs & derivatives / Q000494:pharmacology; D050598:Vesicular Glutamate Transport Protein 1 / Q000378:metabolism; D005680:gamma-Aminobutyric Acid / Q000494:pharmacology
chemical_list: D000588:Amines; D017077:Culture Media, Conditioned; D003509:Cyclohexanecarboxylic Acids; D018690:Excitatory Amino Acid Agonists; D018691:Excitatory Amino Acid Antagonists; D009419:Nerve Tissue Proteins; D047428:Protein Kinase Inhibitors; D011810:Quinoxalines; D018091:Receptors, AMPA; D013873:Thionucleotides; D019699:Thrombospondins; D050598:Vesicular Glutamate Transport Protein 1; C062865:2,3-dioxo-6-nitro-7-sulfamoylbenzo(f)quinoxaline; C016957:adenosine-3',5'-cyclic phosphorothioate; C058394:2-chloro-N(6)cyclopentyladenosine; D005680:gamma-Aminobutyric Acid; D016202:N-Methylaspartate; D011189:Potassium Chloride; D000077206:Gabapentin; C056639:2-amino-5-phosphopentanoic acid; D000242:Cyclic AMP; D050882:CREB-Binding Protein; D034284:Dynamin I; D014633:Valine; D000241:Adenosine; C104722:glutamate receptor ionotropic, AMPA 2