GLT-1 down-regulation induced by clozapine in rat frontal cortex is associated with synaptophysin up-regulation.
In rat frontal cortex, extracellular levels of glutamate are raised by the anti-psychotic drug clozapine. We have recently shown that a significant reduction in the levels of the glutamate transporter GLT-1 may be one of the mechanisms responsible for this elevation. Here we studied whether GLT-1 down-regulation induced by chronic clozapine treatment is associated with changes in the expression of synaptophysin, synaptosome-associated protein of 25 kDa (SNAP-25) and vesicular glutamate transporter 1 (VGLUT1), three major presynaptic proteins involved in neurotransmitter release. Quantitative high-resolution confocal microscopy studies in vivo showed that GLT-1 down-regulation is closely associated with a significant increase in synaptophysin, but not SNAP-25 and VGLUT1, expression. This was confirmed in vitro studies, and in western blotting studies of synaptophysin, SNAP-25 and VGLUT1. In addition, our results show that, following clozapine treatment, synaptophysin expression increases in the very cortical regions in which GLT-1 expression is down-regulated. These findings suggest that part of the effects of clozapine may be exerted via an action on the presynaptic machinery involved in neurotransmitter release.
Bragina
Luca
L
Dipartimento di Neuroscienze, Sezione di Fisiologia, Università Politecnica delle Marche, Ancona, Italy.
Melone
Marcello
M
Fattorini
Giorgia
G
Torres-Ramos
Monica
M
Vallejo-Illarramendi
Ainara
A
Matute
Carlos
C
Conti
Fiorenzo
F
D000818:Animals; D001253:Astrocytes / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D003024:Clozapine / Q000494:pharmacology*; D018920:Coculture Techniques; D027342:Excitatory Amino Acid Transporter 2 / Q000235:genetics*; D005625:Frontal Lobe / Q000187:drug effects / Q000502:physiology*; D005786:Gene Expression Regulation / Q000187:drug effects*; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D016708:Synaptophysin / Q000235:genetics*; D050825:Synaptosomal-Associated Protein 25 / Q000235:genetics; D050598:Vesicular Glutamate Transport Protein 1 / Q000235:genetics
D027342:Excitatory Amino Acid Transporter 2; C493466:Slc17a7 protein, rat; C494210:Snap25 protein, rat; D016708:Synaptophysin; D050825:Synaptosomal-Associated Protein 25; D050598:Vesicular Glutamate Transport Protein 1; D003024:Clozapine