Abstract
A selective serotonin reuptake inhibitor is the most commonly prescribed antidepressant for the treatment of major depression. However, the mechanisms underlying the actions of selective serotonin reuptake inhibitors are not fully understood. In the dentate gyrus, chronic fluoxetine treatment induces increased excitability of mature granule cells (GCs) as well as neurogenesis. The major input to the dentate gyrus is the perforant path axons (boutons) from the entorhinal cortex (layer II). Through voltage-sensitive dye imaging, we found that the excitatory neurotransmission of the perforant path synapse onto the GCs in the middle molecular layer of the mouse dentate gyrus (perforant path-GC synapse) is enhanced after chronic fluoxetine treatment (15 mg/kg/day, 14 days). Therefore, we further examined whether chronic fluoxetine treatment affects the morphology of the perforant path-GC synapse, using FIB/SEM (focused ion beam/scanning electron microscopy). A three-dimensional reconstruction of dendritic spines revealed the appearance of extremely large-sized spines after chronic fluoxetine treatment. The large-sized spines had a postsynaptic density with a large volume. However, chronic fluoxetine treatment did not affect spine density. The presynaptic boutons that were in contact with the large-sized spines were large in volume, and the volumes of the mitochondria and synaptic vesicles inside the boutons were correlated with the size of the boutons. Thus, the large-sized perforant path-GC synapse induced by chronic fluoxetine treatment contains synaptic components that correlate with the synapse size and that may be involved in enhanced glutamatergic neurotransmission.
Highlights
Major depressive disorder is one of the most common psychiatric disorders, but the efficacy of antidepressant medication is not sufficient [1, 2]
Neural activity of perforant path synapses in the dentate gyrus (DG) after chronic fluoxetine treatment The spatiotemporal propagation of neuronal excitation was recorded from neurons in the middle molecular layer of the hippocampal DG, where the perforant path inputs from layer II of the entorhinal cortex form synaptic connections with the dendritic spines of granule cells (GCs) (S1A–S1C Fig)
The application of a single electrical stimulation (30 V for 400 μs) to the perforant path inputs in the middle molecular layer of the DG resulted in depolarizing optical responses adjacent to the stimulated site with a latency of 1.2 ms and their spreading in the middle molecular layer (Fig 1A and S1C Fig)
Summary
Major depressive disorder is one of the most common psychiatric disorders, but the efficacy of antidepressant medication is not sufficient [1, 2]. The monoamine and monoamine receptor hypotheses of depression were derived from analyses of antidepressant action [3], but the PLOS ONE | DOI:10.1371/journal.pone.0147307. Antidepressants were recently shown to increase the excitability of mature granule cells (GCs) in the DG and to reduce the expression of mature GC markers such as calbindin and tryptophan-2,3-dioxygenase [12]. These observations suggest that the DG may be one of the therapeutic targets of antidepressants
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