Serotonin-containing terminals synapse on septohippocampal neurons in the rat

Serotonin [5-hydroxytryptamine (5-HT)] is thought to be involved in mnemonic functions and dysfunctions possibly by directly contacting neurons in the medial septal and diagonal band nuclei (i.e., the septal complex) that project to the hippocampal formation. However, there is no cellular substrate for this modulation. Thus, we examined the ultrastructure and synaptic associations of 5-HT-containing terminals in relation to septohippocampal neurons in the septal complex of the rat brain. Projection neurons were identified by retrograde transport of wheat germ agglutinated apo-horseradish peroxidase conjugated to colloidal gold particles (WAHG) following an injection into the ventral hippocampal formation of anesthetized adult rats. After a 1 day survival, sections through the septal complex were labeled with antibodies to 5-HT. By light microscopy, numerous processes with 5-HT immunoreactivity (5-HT-I) were observed in close proximity to neurons containing retrogradely transported WAHG. By electron microscopy, 5-HT-I was found exclusively in axons and axon terminals. Axons were primarily unmyelinated. Terminals with 5-HT-I were 0.35-1.2 microns in diameter and contained numerous small, clear vesicles and 0-4 large, dense-core vesicles. The 5-HT-labeled terminals: 1) contacted perikarya and dendrites (220 of 349); 2) were closely apposed to other terminals (25 of 349); or 3) had no neuronal contacts in the plane of section analyzed (104 of 349). The 5-HT-labeled terminals formed exclusively symmetric synapses on perikarya; some of these perikarya as well as some large dendrites similarly contacted by the 5-HT-labeled terminals also contained WAHG affiliated with lysosomes and multivesicular and "sequestration" bodies in the cytoplasm. However, the majority of terminals with 5-HT-I formed contacts on the shafts of small unlabeled dendrites (69% of 220); most of these were characterized as either asymmetric synapses or appositions not separated by astrocytes in the plane of section analyzed. We conclude that 5-HT-containing terminals in the rat septal complex: 1) directly modulate septohippocampal and other neurons through symmetric (potentially inhibitory) synapses on soma and proximal dendrites; and 2) form primarily asymmetric (potentially excitatory) synapses with distal (small) dendrites from neurons of unidentified origin. These findings suggest that serotonin may affect learning and memory through modulation of septal efferents to the hippocampal formation and may have direct relevance to the neuropathological basis for Alzheimer's disease.