Ultrastructural localization of the serotonin transporter in superficial and deep layers of the rat prelimbic prefrontal cortex and its spatial relationship to dopamine terminals

Abstract

Dopamine levels within the prefrontal cortex (PFC) can be manipulated by selective inhibitors of the serotonin transporter (SERT). However, the cellular mechanisms underlying these effects are not clear. The present study sought to examine the distribution of immunogold-silver labeling for SERT (SERT-ir) in the rat prelimbic PFC and to describe its ultrastructural spatial relationship to dopamine axons labeled by immunoperoxidase staining for tyrosine hydroxylase (TH-ir). SERT was localized to axonal profiles that ranged in size from fine caliber fibers containing dense SERT-ir, primarily along the membrane, and rarely forming synapses to large, spherical varicosities exhibiting less dense staining, mainly within the cytoplasm, and more commonly forming synapses. Synaptic contacts of SERT profiles were typically asymmetric, axospinous, and more frequent in superficial (38%) than deep (19%) layers. For TH-ir profiles, only 24% were within the same 13.8 microm(2) microenvironment as SERT-ir profiles. Furthermore, TH-ir and SERT-ir profiles were rarely directly apposed to each other or convergent onto common dendritic structures. Instead, these two profiles were typically separated by an average distance of 1.30 microm in the coronal plane, a value that did not vary with the size of SERT-ir axons, the amount of SERT labeling, or the cortical layer examined. These results are consistent with two populations of SERT profiles within the rat prelimbic PFC that may arise from different raphe nuclei or that represent varicose and intervaricose portions of the same axons. Moreover, the functional interactions between cortical serotonin and dopamine systems that may contribute to the therapeutic efficacy of antidepressant drugs are likely to occur over distances greater than 1 microm.

Excitatory/inhibitory balance of serotonergic axon connectivity in the brain

“…These contacts were essentially asymmetric on dendritic spines and branches. Similar results were observed in rat frontoparietal cortex using Tryptophan hydroxylase (TPH) immunolabelling 14 or in the prefrontal cortex using SERT immunolabelling 15 .…”

Psychedelics

“…Séguéla et al (1989) estimated that only about 38% of serotonin axons in the cortex engaged in synaptic contact. Furthermore, serotonin reuptake transporters are frequently located at extrasynaptic sites in the PFC (Miner et al, 2000). On the basis of their results as well as other data, Miner et al (2003) proposed that cortical 5-HT innervation is primarily nonjunctional and that the entire cortical volume may be reached by serotonin.…”

Neuroimaging research in human MDMA users: a review

“…The 5-HTT is distributed along the entire course of 5-HT axons rather than solely at the synaptic terminal (Zhou et al 1998;Miner et al 2000). As a result, loss of serotonergic axons would be predicted to result in reduced levels of the 5-HTT in affected regions, providing an intriguing target marker to investigate MDMA-induced axon toxicity.…”