Research article summary (published 30 Aug 2008):

Efficient copackaging and cotransport yields postsynaptic colocalization of neuromodulators associated with synaptic plasticity.

Full Abstract

Recent data suggest that tissue plasminogen activator (tPA) influences long-term plasticity at hippocampal synapses by converting plasminogen into plasmin, which then generates mature brain-derived neurotrophic factor (mBDNF) from its precursor, proBDNF. Motivated by this hypothesis, we used fluorescent chimeras, expressed in hippocampal neurons, to elucidate (1) mechanisms underlying plasminogen secretion from hippocampal neurons, (2) if tPA, plasminogen, and proBDNF are copackaged and cotransported in hippocampal neurons, especially within dendritic spines, and (3) mechanisms mediating the transport of these neuromodulators to sites of release. We find that plasminogen chimeras traffic through the regulated secretory pathway of hippocampal neurons in dense-core granules (DCGs) and that tPA, plasminogen, and proBDNF chimeras are extensively copackaged in DCGs throughout hippocampal neurons. We also find that 80% of spines that contain DCGs contain chimeras of these neuromodulators in the same DCG. Finally, we demonstrate, for the first time, that neuromodulators undergo cotransport along dendrites in rapidly mobile DCGs, indicating that neuromodulators can be efficiently recruited into active spines. These results support the hypothesis that tPA mediates synaptic activation of BDNF by demonstrating that tPA, plasminogen, and proBDNF colocalize in DCGs in spines, where these neuromodulators can undergo activity-dependent release and then interact and/or mediate changes that influence synaptic efficacy. The results also raise the possibility that frequency-dependent changes in extents of neuromodulator release from DCGs influence the direction of plasticity at hippocampal synapses by altering the relative proportions of two proteins, mBDNF and proBDNF, that exert opposing effects on synaptic efficacy.

Author information

Author/s: Lochner, J E (JE); Spangler, E (E); Chavarha, M (M); Jacobs, C (C); McAllister, K (K); Schuttner, L C (LC); Scalettar, B A (BA);

Affiliation: Department of Chemistry, Lewis & Clark College, Portland, Oregon 97219, USA.

Grants: 2 R15 GM061539-02 (Agency:NIGMS NIH HHS) ; 2 R15 NS40425-02 (Agency:NINDS NIH HHS) ; MH 66179 (Agency:NIMH NIH HHS)

Journal and publication information

Publication Type: Journal Article; Research Support, N.I.H., Extramural

Journal: Developmental neurobiology (Dev Neurobiol), published in United States. (Language: eng)

Reference: 2008-Sep; vol 68 (issue 10) : pp 1243-56

Dates: Created 2008/07/23; Completed 2008/10/20;

PMID: 18563704, status: MEDLINE (last retrieval date: 2/18/2009, IMS Date: )

Sourced from the National Library of Medicine. Abstract text and other information may be subject to copyright.

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MeSH headings (categories)

This article was linked to the MESH Headings shown below.

Animals Axonal Transport - physiology Brain-Derived Neurotrophic Factor - metabolism Cells, Cultured Dendritic Spines - metabolism; ultrastructure Hippocampus - cytology; metabolism Neuronal Plasticity - physiology Neurons - cytology; metabolism; secretion

Neurotransmitter Agents - metabolism; secretion Plasminogen - metabolism Protein Transport - physiology Rats Secretory Vesicles - metabolism Synapses - metabolism Synaptic Transmission - physiology Tissue Plasminogen Activator - metabolism

Associated Chemicals: Brain-Derived Neurotrophic Factor (0) ; Neurotransmitter Agents (0) ; Plasminogen (9001-91-6) ; Tissue Plasminogen Activator (EC 3.4.21.68)

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