Tissue‐type plasminogen activator‐plasmin‐BDNF modulate glutamate‐induced phase‐shifts of the mouse suprachiasmatic circadian clock in vitro

Abstract

The mammalian circadian clock in the suprachiasmatic nucleus (SCN) maintains environmental synchrony through light signals transmitted by glutamate released from retinal ganglion terminals. Brain-derived neurotrophic factor (BDNF) is required for light/glutamate to reset the clock. In the hippocampus, BDNF is activated by the extracellular protease, plasmin, which is produced from plasminogen by tissue-type plasminogen activator (tPA). We provide data showing expression of proteins from the plasminogen activation cascade in the SCN and their involvement in circadian clock phase-resetting. Early night glutamate application to SCN-containing brain slices resets the circadian clock. Plasminogen activator inhibitor-1 (PAI-1) blocked these shifts in slices from wild-type mice but not mice lacking its stabilizing protein, vitronectin (VN). Plasmin, but not plasminogen, prevented inhibition by PAI-1. Both plasmin and active BDNF reversed alpha(2)-antiplasmin inhibition of glutamate-induced shifts. alpha(2)-Antiplasmin decreased the conversion of inactive to active BDNF in the SCN. Finally, both tPA and BDNF allowed daytime glutamate-induced phase-resetting. Together, these data are the first to demonstrate expression of these proteases in the SCN, their involvement in modulating photic phase-shifts, and their activation of BDNF in the SCN, a potential 'gating' mechanism for photic phase-resetting. These data also demonstrate a functional interaction between PAI-1 and VN in adult brain. Given the usual association of these proteins with the extracellular matrix, these data suggest new lines of investigation into the locations and processes modulating mammalian circadian clock phase-resetting.

Localization of plasminogen in mouse hippocampus, cerebral cortex, and hypothalamus

“…Microarray studies have shown that tPA, plasminogen, and plasminogen-activator-inhibitor-1 (PAI-1) mRNAs are expressed in the SCN, with tPA and PAI-1 mRNAs showing rhythmic expression (Panda et al 2002). tPA-plasminogen-BDNF modulates glutamateinduced phase-shifts of the circadian clock in cultured suprachiasmatic neurons (Mou et al 2009). The SCN is anatomically and functionally organized into two subdivisions: a core that lies adjacent to the optic chiasm, and a shell that surrounds the core in its dorsomedial portion.…”

Shared Immune and Repair Markers During ExperimentalToxoplasmaChronic Brain Infection and Schizophrenia

“…56 Increased levels of PAI-1 may also be linked to reduced neurotrophic support in the brain of schizophrenia patients, because PAI-1 is involved in brainderived neurotrophic factor maturation in the hippocampus. 57 Nevertheless, further studies are required to investigate the exact impact of elevated PAI-1 on brain function.…”

Proteolytic cleavage of proBDNF into mature BDNF in the basolateral amygdala is necessary for defeat-induced social avoidance

“…Animals were euthanized 1 or 2 h following social defeat or empty cage exposure, and tissue punches were collected bilaterally from the BLA/CeA. Western blot assays for proBDNF and mBDNF were performed as previously described (Mou et al 2009). A detailed Methods section is provided as Supplemental Material.…”