Chronic fluoxetine treatment increases expression of synaptic proteins in the hippocampus of the ovariectomized rat: role of BDNF signalling.
Antidepressant drugs have been suggested to regulate synaptic transmission and structure. We hypothesised that antidepressant-induced changes in synapses and their associated proteins might become more apparent if they were measured under conditions of reduced synapse density. Therefore, in the present study, we examined whether chronic treatment with the antidepressant, fluoxetine alters expression of synaptic proteins in the hippocampus of rodents that underwent ovariectomy, a procedure which reportedly decreases synapse density in the CA1 region of the rat hippocampus. Using Western blotting, we measured changes in hippocampal expression of proteins associated with synapse structure, strength and activity namely, postsynaptic density protein 95 (PSD-95), the alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPA-R) subunit GluR1 and phosphosynapsin (Ser9), respectively. We found that fluoxetine treatment increased expression of phosphosynapsin, PSD-95 and synaptic GluR1 (but not total GluR1) in the hippocampus of ovariectomized but not sham rats. Since BDNF and signalling at its receptor, TrkB, can mediate behavioural responses to antidepressants and induce neuronal plasticity, we investigated the contribution of TrkB signalling to fluoxetine-induced changes in synaptic protein expression by using a transgenic mouse model overexpressing a truncated form of the TrkB receptor (TrkB.T1). Fluoxetine produced a small but significant increase in hippocampal PSD-95 in ovariectomized wildtype mice but not in ovariectomized TrkB.T1 mice or sham mice. In contrast to rats, fluoxetine did not alter expression of synaptic GluR1 and did not reverse ovariectomy-induced decreases in hippocampal phosphosynapsin in either genotype. Taken together, these results suggest that chronic fluoxetine treatment can increase synaptic protein expression in the hippocampus and at least some of these effects require TrkB signalling. Moreover, these effects were only observed in ovariectomized animals, thus suggesting that fluoxetine-induced increases in synaptic protein levels might only occur or become detectable when hippocampal synaptic connectivity is perturbed.
O'Leary
Olivia F
OF
Neuroscience Centre, University of Helsinki, Finland. Olivia.oleary@helsinki.fi
Wu
Xuefei
X
Castren
Eero
E
D000818:Animals; D018687:Antidepressive Agents, Second-Generation / Q000008:administration & dosage / Q000494:pharmacology; D001835:Body Weight / Q000187:drug effects; D000076122:Disks Large Homolog 4 Protein; D005260:Female; D005473:Fluoxetine / Q000008:administration & dosage / Q000494:pharmacology*; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism*; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009929:Organ Size / Q000187:drug effects; D010052:Ovariectomy; D051381:Rats; D017207:Rats, Sprague-Dawley; D020813:Receptor, trkB / Q000235:genetics / Q000378:metabolism*; D018091:Receptors, AMPA / Q000378:metabolism; D017981:Receptors, Neurotransmitter / Q000378:metabolism*; D015398:Signal Transduction; D016704:Synapsins / Q000378:metabolism; D014599:Uterus / Q000187:drug effects
D018687:Antidepressive Agents, Second-Generation; D000076122:Disks Large Homolog 4 Protein; D005473:Fluoxetine; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D020813:Receptor, trkB; D018091:Receptors, AMPA; D017981:Receptors, Neurotransmitter; D016704:Synapsins; C501449:Dlg4 protein, rat