Abstract
Antidepressant drugs are usually administered for several weeks for the treatment of major depressive disorder. However, they are also prescribed in several additional psychiatric conditions as well as during long-term maintenance treatments. Antidepressants induce adaptive changes in several forebrain structures which include modifications at glutamatergic synapses. We recently found that repetitive administration of the selective serotonin reuptake inhibitor (SSRI) fluoxetine to naïve adult male rats induced an increase of mature, mushroom-type dendritic spines in several forebrain regions. This was associated with an increase of GluA2-containing α-amino-3-hydroxy-5-methylisoxazole-4-propionate receptors (AMPA-Rs) in telencephalic postsynaptic densities. To unravel the functional significance of such a synaptic re-arrangement, we focused on glutamate neurotransmission in the hippocampus. We evaluated the effect of four weeks of 0.7 mg/kg fluoxetine on long-term potentiation (LTP) and long-term depression (LTD) in the CA1 hippocampal subfield. Recordings in hippocampal slices revealed profound deficits in LTP and LTD at Schaffer collateral-CA1 synapses associated to increased spine density and enhanced presence of mushroom-type spines, as revealed by Golgi staining. However, the same treatment had neither an effect on spine morphology, nor on LTP and LTD at perforant path-CA1 synapses. Cobalt staining and immunohistochemical experiments revealed decreased AMPA-R Ca2+ permeability in the stratum radiatum (s.r.) together with increased GluA2-containing Ca2+ impermeable AMPA-Rs. Therefore, 4 weeks of fluoxetine treatment promoted structural and functional adaptations in CA1 neurons in a pathway-specific manner that were selectively associated with impairment of activity-dependent plasticity at Schaffer collateral-CA1 synapses.
Highlights
Fluoxetine is a selective serotonin reuptake inhibitor (SSRI) that is widely used to treat anxiety- and mood-related disorders, but in addition, its use has been expanded to other psychiatric conditions and is often continued after remission of symptoms (Schatzberg, 2000; Blier et al, 2007)
To study the effect of fluoxetine on cellular plasticity, we focused on CA1 pyramidal neurons which receive spatially segregated direct and indirect excitatory inputs from the entorhinal cortex (EC) via the perforant path and the Schaffer collaterals originating in CA3, respectively
While Schaffer collaterals terminate in the CA1 stratum radiatum (s.r.) on proximal dendrites, the direct perforant path makes synapses on the distal dendrites of CA1 neurons that are localized in the stratum lacunosum moleculare (s.l.m.) (Steward, 1976)
Summary
Fluoxetine is a selective serotonin reuptake inhibitor (SSRI) that is widely used to treat anxiety- and mood-related disorders, but in addition, its use has been expanded to other psychiatric conditions and is often continued after remission of symptoms (Schatzberg, 2000; Blier et al, 2007). It has been shown that the activation of gene transcription following fluoxetine treatment is elicited by epigenetic remodeling of chromatin structure leading to increased plasticity and dendritic spine remodeling (Maya Vetencourt et al, 2011; Wang et al, 2011) This has been proposed to underlie plastic changes in glutamate neurotransmission (Pittenger and Duman, 2008; Sanacora et al, 2008; Maya-Vetencourt et al, 2012). It had been previously described by us that 28 days of 0.7 mg/kg fluoxetine administration to adult naïve rats induced growth of dendritic spines and changes in glutamate receptor subunit composition in cerebrocortical synapses (Ampuero et al, 2010). While Schaffer collaterals terminate in the CA1 stratum radiatum (s.r.) on proximal dendrites, the direct perforant path makes synapses on the distal dendrites of CA1 neurons that are localized in the stratum lacunosum moleculare (s.l.m.) (Steward, 1976)
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