The effect of central cholinergic and noradrenergic denervation on hippocampal sympathetic ingrowth and apoptosis-like reactivity in the rat

Abstract

In this study, the effect of intraseptal injection of specific cholinotoxin 192-IgG saporin (SAP) ± intraperitoneal injection of N-[chloroethyl]- N-ethyl-2-bromobenzylamine (DSP-4) (noradrenergic fiber neurotoxin) was examined in rat hippocampus. Medial septal lesions resulted not only in selective cholinergic denervation of hippocampus (Medial septal lesion + ganglionectomy; SAP + Gx) but also in hippocampal sympathetic ingrowth (IG) of adrenergic fibers (Medial septal lesion + sham ganglionectomy; SAP + IG). Saporin-induced septal lesions produced a significant reduction in hippocampal choline acetyltransferase activity in all tested groups (SAP + IG ± DSP-4 and SAP + Gx ± DSP-4), and an increase in noradrenaline concentration in the SAP + IG group. Visualization of noradrenergic fibers by histofluorescence revealed a mixture of fine and thick varicosities in the SAP + IG but only fine fibers in control and SAP + Gx animals. SAP + IG + DSP-4 lesions produced significant reduction in noradrenaline concentration in all groups with a concomitant decrease in visualization of central noradrenergic fibers in dorsal and ventral hippocampus. Treatment of SAP + IG animals with DSP-4 left mostly thick fibers, probably derived from peripheral sympathetic ingrowth. No fluorescence was seen in either the control + DSP-4 or SAP + Gx + DSP-4 animals. Apoptotic-like changes, using in situ oligonucleotide ligation techniques, were also assessed. Proapoptotic changes were seen in the SAP + Gx ± DSP-4 group as compared to CON ± DSP-4 groups. SAP + IG regardless of DSP-4 treatment protected hippocampal cells from apoptotic cell death when compared to positive control and SAP + Gx ± DSP-4 groups. In summary, elevated noradrenaline concentration following specific cholinergic denervation probably reflects compensatory hippocampal ingrowth originating from the peripheral sympathetic system which may be responsible for neuroprotective effects, i.e., antiapoptosis-like effect. Since cholinergic and noradrenergic systems are known to be involved in Alzheimer's disease and related cognitive function, knowing how these neurotransmitters work after specific lesions may be of importance as an animal model of Alzheimer's disease and as a potential target for Alzheimer's disease drug therapies.