Abstract
Serotonin neurons arise from the brainstem raphe nuclei and send their projections throughout the brain to release 5-HT which acts as a modulator of several neuronal populations. Previous electron microscopy studies in rats have morphologically determined the distribution of 5-HT release sites (boutons) in certain brain regions and have shown that 5-HT containing boutons form synaptic contacts that are either symmetric or asymmetric. In addition, 5-HT boutons can form synaptic triads with the pre- and postsynaptic specializations of either symmetrical or asymmetrical synapses. However, due to the labor intensive processing of serial sections required by electron microscopy, little is known about the neurochemical properties or the quantitative distribution of 5-HT triads within whole brain or discrete subregions. Therefore, we used a semi-automated approach that combines immunohistochemistry and high-resolution confocal microscopy to label serotonin transporter (SERT) immunoreactive axons and reconstruct in 3D their distribution within limbic brain regions. We also used antibodies against key pre- (synaptophysin) and postsynaptic components of excitatory (PSD95) or inhibitory (gephyrin) synapses to (1) identify putative 5-HTergic boutons within SERT immunoreactive axons and, (2) quantify their close apposition to neurochemical excitatory or inhibitory synapses. We provide a 5-HTergic axon density map and have determined the ratio of synaptic triads consisting of a 5-HT bouton in close proximity to either neurochemical excitatory or inhibitory synapses within different limbic brain areas. The ability to model and map changes in 5-HTergic axonal density and the formation of triadic connectivity within whole brain regions using this rapid and quantitative approach offers new possibilities for studying neuroplastic changes in the 5-HTergic pathway.
Highlights
Serotonin (5-hydroxytryptamine, 5-HT) is a neuromodulator extensively implicated in the regulation of mood, emotion, sleep and appetite
Studies have shown that 5-HTergic boutons may synapse to either the pre- or postsynaptic components of GABA/glycinergic (Fig. 1a-4) or accumbens core and the medial shell (NACc and nucleus accumbens shell (NACs), bregma 1.18 ± 0.3 mm), the ventromedial and posterolateral part of the bed nucleus of the stria terminalis (BNST, bregma 0.18 ± 0.2 mm), the basolateral and central amygdala (BLA and CeA, bregma -1.46 ± 0.4 mm), the strata oriens of the CA3 region of the hippocampus (HIP, bregma -1.46 ± 0.4 mm) and the ventral tegmental area (VTA, bregma -2.92 ± 0.2 mm) (Fig. 1b)
We found that serotonin transporter (SERT)? fibers have an average diameter of 0.645 ± 0.007 lm in the medial prefrontal cortex (mPFC), 0.689 ± 0.017 lm in the NACs, 0.687 ± 0.009 lm in the NACc, 0.652 ± 0.008 lm in the BNST, 0.742 ± 0.006 lm in the BLA, 0.712 ± 0.004 lm in the CeA, 0.715 ± 0.008 lm in the HIP and
Summary
Serotonin (5-hydroxytryptamine, 5-HT) is a neuromodulator extensively implicated in the regulation of mood, emotion, sleep and appetite. Alterations in 5-HTergic neuronal signaling contribute to various neuropsychiatric disorders such as anxiety, major depression and drug abuse. Serotonin neurons arising from the brainstem raphe nuclei send their projections throughout the brain to form direct synapses with the neuropil of the targeted neurons. 5-HT is diffusely released by ‘‘volume transmission’’ (extra-synaptic) in several brain regions and initiates neuromodulatory activity of excitatory and inhibitory synapses in contrast to ‘‘classical’’ neurotransmitters (Bunin and Wightman 1998; De-Miguel and Trueta 2005; Kiss 2008). 5-HT neurons contact glutamatergic or GABAergic/glycinergic synapses to form synaptic triads that modulate the activity of excitatory or inhibitory synapses (For review, see Ciranna 2006).
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