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Published byGilbert Roberts Modified over 6 years ago
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Contributions of BDNF to the Maturation of Cortical Inhibitory Circuits
Ali Hamodi
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Introduction BDNF: Brain-Derived Neurotrophic Factor
A member of the neurotrophin family Plays important roles ranging from cell survival to cell death Important in modulating synaptic morphology and activity (McAllister et al, 1997) Little is known about how BDNF contributes to activity-dependent remodeling of inhibitory synapses -Excitatory cells vs. inhibitory cells -While neurotrophin’s modulation of synaptic morphology and activity has been extensively studied in dissociated cells and slice cultures, little is known about how BDNF contributes to the activity-dependent remodeling of inhibitory synapses in vivo. -Roles of BDNF: cell survival apoptosis gene expression synaptic plasticity, neurotransmitter release in the CNS, and cellular outgrowth
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Hypothesis Local BDNF mediates long-lasting intracellular calcium mobilization in neonatal GABAergic interneurons Goal What are the cellular and pharmacological properties of BDNF-induced long-lasting intracellular calcium?
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Methods Brain-slice cutting Brain-slice Incubation
Immunohistochemistry C-fos/DAB staining Immunoflourescent labeling Data analysis Counting cell density using Axiovision software Computer-aided cell reconstruction using Neurolucida software
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What are the cellular and pharmacological properties of BDNF-induced long-lasting intracellular calcium? Pharmacological agents used K252a: Receptor tyrosine kinase inhibitor SKF96365: TRPC inhibitor MRS1845: Capacitative Ca+2 inhibitor LOE908: Broad-spectrum cation channel blocker 2-APB: IP3 antagonist U73122: Phospholipase C inhibitor Thapsigargin: SERCA ATPase inhibitor KB-R7943: TPRC and Na+/Ca2+ exchanger Suramin: Broad-spectrum antagonist of P2 receptors (ATP receptors) and agonist of Ryanodine receptors PPDA: NMDAR antagonist
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Results *
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Results
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Results P=
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Results Antagonist Effective TrkB inhibitor Yes TRPC inhibitor
Capacitative Ca2+ inhibitor No Broad-spectrum cation channel blocker No IP3 antagonist PLC inhibitor SERCA ATPase inhibitor TRPC and Na+/Ca2+ exchanger Broad-spectrum antagonist of P2 receptors and agonist of Ryanodine receptors NMDAR antagonist
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BDNF & GABAergic interneurons
GAD67-GFP C-fos DAPI Merged
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Summary What are the cellular and pharmacological properties of BDNF-induced long-lasting increase in intracellular calcium? BDNF plays a role in activity-dependent remodeling of GABAergic cells through c-fos expression BDNF-induced signaling cascade initiated by BDNF/TrkB interaction Ca2+ influx mainly mediated by release from intracellular stores IP3 SERCA pumps Secondary effect of Ca2+ influx through TRPC channels
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Health Relevance BDNF’s role in neuronal development and maturation of cognitive function (Hong et al, 2005) Deficits Epilepsy Rhett Syndrome Schizophrenia Autism spectrum disorders -BDNF knockout mice had major cortical cytoarchitechtural deficit and die at birth; -BDNF overexpression mice exhibited precautious maturation of cortical inhibitory circuits and disturbed visual critical period formation. -Schizophrenic patients have decreased BDNF &TrkB -Autism: decreased BDNF
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QUESTIONS??
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