Intraocular Neurografts as a Model for Studying of Organization of Synaptic Connections in a Denervated Brain Area.

Intraocular neurografts of the septal region of rats were used as the model of deafferentiated brain area where the lack of adequate innervation is compensated for own interneuronal connections. Septum anlage from the brain of a 17-day fetus served as the donor material. The grafts developing in the anterior eye chamber over 3 months represented well-differentiated samples of the nervous tissue. A comparative morphometric study of the tripartite organization of synapses in the grafts and in the septum in situ was conducted. In the grafts, the mean volume and perimeter of synaptic terminals were below the normal. At the same time, postsynaptic densities did not differ from the control. A significant difference was found in the degree of surrounding of presynaptic terminals by astrocytic processes: in the grafts this parameter was higher by 1.8 times. Our results attest to an important role of perisynaptic glia in the formation of functionally active synaptic contacts with unusual neuronal targets.

Outcomes after endonasal septoplasty using caudal septal batten grafting.

BACKGROUND: This study evaluated surgical outcomes after endonasal septoplasty using caudal septal batten grafting for caudal septal deviation. METHODS: Fifty-six patients completed questionnaires to assess nasal obstruction by telephone interviews 8-63 months postoperatively (12.2 months on the average). In addition, patients assessed the severity of nasal symptoms (i.e., mouth breathing, mouth dryness, hyposmia, rhinorrhea, epistaxis, trouble sleeping, snoring, and being concerned about nasal problems) preoperatively and postoperatively using a visual analog scale (VAS). These VAS scores were compared with those of patients who underwent endonasal septoplasty using the cutting and suture technique. Complications were analyzed. RESULTS: Thirty-four (60.7%) patients reported their nasal obstruction was much improved, 17 (30.3%) reported their condition was improved, and 5 (8.9%) reported no change postoperatively. Patients reported a decrease in severity of all nasal symptoms (p < 0.05 for each). Their nasal obstruction improvement was not significantly different from that of patients managed by the cutting and suture technique. Complications after surgery included hyposmia in two cases, small septal perforation in one case, chondritis in one case, and septal abscess in one case, and all were managed successfully. No patient required revision septoplasty due to recurrence during the follow-up period. CONCLUSION: Endonasal septoplasty using caudal septal batten grafting for caudal septal deviation resulted in improvement in nasal obstruction and nasal symptoms and was associated with an acceptable complication rate.

Septal grafts restore cognitive abilities and amyloid precursor protein metabolism.

Cortical cholinergic loss and amyloidogenic processing of the beta-amyloid precursor protein (APP), may functionally interact in Alzheimer's disease. However, it is still unknown whether biological restoration of regulatory cholinergic inputs affects APP metabolism in vivo. Rats immunolesioned with 192 IgG-saporin exhibited severe acquisition deficits in place navigation that were paralleled by a dramatic loss of terminal cholinergic innervation and by marked changes in the regional expression of APP-like immunoreactivity. Moreover, in these animals, we observed a drastic reduction of soluble APP (sAPP) and a concomitant increase of the unsoluble, membrane-bound fraction (mAPP). Notably, at about 6 months post-surgery, lesioned animals implanted with reinnervating cholinergic-rich septal tissue grafts exhibited fairly normal spatial navigation abilities, as well as cortical and hippocampal APP levels that were restored up to normal or near-normal values. APP levels correlated significantly with lesion- or graft-induced changes in cholinergic innervation density, and both these measures correlated with performance in the spatial navigation task. Thus, integrity of ascending cholinergic inputs may be required to prevent amyloidogenic processing of APP in vivo and to modulate cognitive performance.

Regulation of trophic factor expression by innervating target regions in intraocular double transplants.

Trophic factors have been found to play a significant role both in long-term survival processes and in more rapid and dynamic processes in the brain and spinal cord. However, little is known regarding the regulation of expression of growth factors, and how these proteins interact on a cell-to-cell basis. We have studied protein levels of one growth factor known to affect the noradrenergic innervation of the hippocampal formation, namely brain-derived neurotrophic factor (BDNF). The purpose of the present study was to determine if appropriate innervation or contact between the LC noradrenergic neurons and their target, the hippocampus, affects expression of this growth factor in either brain region. Fetal brain stem tissue, containing the LC, and hippocampal formation were dissected from embryonic day 17 rat fetuses and transplanted together or alone into the anterior chamber of the eye of adult Fisher 344 rats. The tissue was grown together for 6 weeks, after which the animals were sacrificed and ELISAs for BDNF were undertaken. Transplantation to the anterior chamber of the eye increased the expression of BDNF in the hippocampal but not the brain stem tissue, compared with levels observed in fetal and adult rats in vivo. In addition, double grafting with hippocampal tissue more than tripled BDNF levels in brain stem grafts and doubled BDNF levels in the hippocampal portion of double grafts compared with hippocampal single grafts. Triple grafts containing basal forebrain, hippocampus, and brain stem LC tissue increased brain stem and hippocampal BDNF levels even further. Colchicine treatment of LC-hippocampal double grafts gave rise to a significant decrease in hippocampal BDNF levels to levels seen in single hippocampal grafts, while only a partial reduction of BDNF levels was seen in the brain stem portion of the same double grafts treated with colchicine. The findings suggest that an appropriate hippocampal innervation or contact with its target tissues is essential for regulation of BDNF expression in the brain stem, and that retrograde transport of BDNF can occur between double grafted fetal tissues in oculo.

Grafts of fetal septal cells after cholinergic immunotoxic denervation of the hippocampus: a functional dissociation between dorsal and ventral implantation sites.

Three-month-old Long-Evans rats were subjected to intraseptal infusions of 0.8 microg of 192 IgG-saporin followed, 2 weeks later, by intrahippocampal suspension grafts containing fetal cells from the medial septum and the diagonal band of Broca. The suspensions were implanted in the dorsal or the ventral hippocampus. Sham-operated and lesion-only rats were used as controls. Between 18 and 32 weeks after grafting, all rats were tested in a water maze (using protocols placing emphasis on reference memory or on working memory) and an eight-arm radial maze. The lesion produced extensive cholinergic denervation of the hippocampus, as evidenced by reduced acetylcholinesterase-positivity and acetylcholine content. Depending upon their implantation site, the grafts restored an acetylcholinesterase-positive reinnervation pattern in either the dorsal or the ventral hippocampus. Nevertheless, the grafts failed to normalize the concentration of acetylcholine in either region. The cholinergic lesion impaired working memory performance in both the water maze and the radial maze. To a limited degree, reference memory was also altered. Grafts placed in the ventral hippocampus had no significant behavioral effect, whereas those placed in the dorsal hippocampus normalized working memory performance in the water maze. Our data show that infusion of 192 IgG-saporin into the septal region deprived the hippocampus of its cholinergic innervation and altered spatial working memory more consistently than spatial reference memory. Although the cholinergic nature of the graft-induced reinnervation remains to be established more clearly, these results further support the idea of a functional dissociation between the dorsal and the ventral hippocampus, the former being preferentially involved in spatial memory.

Septal grafts and evoked acetylcholine release in the rat hippocampus after 192 IgG-saporin lesions.

Adult rats received intraseptal injections of 192 IgG-saporin and intrahippocampal grafts of septal cells. Between 6 and 10 months later, we assessed baseline and electrically-evoked release of tritium in hippocampal slices preloaded with [(3)H]choline, and the uptake of [(3)H]choline, [(3)H]noradrenaline and [(3)H]serotonin by hippocampal synaptosomes. The lesions reduced the accumulation of [(3)H]choline by approximately 40%, the evoked release of [(3)H]acetylcholine by approximately 90%, and the uptake of [(3)H]choline by synaptosomes by 90% in the dorsal hippocampus, but increased the relative baseline release of [(3)H]choline by +43%, and the synaptosomal uptake of [(3)H]noradrenaline (66%) and [(3)H]serotonin (58%) in the ventral hippocampus. The increased noradrenaline uptake may account for sympathetic ingrowth. Although the grafts of fetal septal neurons produced modest cholinergic effects, these effects were positive and significant.

Homotopic grafts of septal neurons combined to polymeric hydrogels placed into a fimbria-fornix lesion cavity attenuate locomotor hyperactivity but not mnemonic dysfunctions in rats.

PURPOSE: We studied the behavioral effects of an intracavitary implantation of poly[N-(2-hydroxypropyl)-methacrylamidel (PHPMA) hydrogels combined to intraseptal grafts of fetal septal cell suspensions in adult female rats subjected to aspirative fimbria-fornix lesions. The hydrogels were used as substrates for bridging the lesion cavity between the septum and the hippocampus. METHODS: Control groups included sham-operated or lesion-only rats, as well as lesioned rats with only the hydrogel bridge in the lesion cavity, only the graft in the septum, or an intrahippocampal graft of a septal cell suspension as a control for the standardly used ectopic transplantation strategy. Up to 10 months after grafting surgery, all rats were tested for locomotor activity in their home cage, sensorimotor performances using a beam-walking test, and cognitive performances in a radial maze, a water maze and a T-maze (rewarded alternation). RESULTS: The lesions induced hyperlocomotion, sensorimotor disturbances and severe alterations of cognitive functions. We found that neither the grafts or the hydrogels, nor the combination of both, induced any significant enhancement of sensorimotor or cognitive performances. Nevertheless, in rats with both intraseptal (homotopic) grafts and a hydrogel implant, the locomotor activity did no longer differ from that found in sham-operated controls. Histological analysis showed that the hydrogels contained acetylcholinesterase(AChE)-positive fibers and that the hippocampal region in contact with the hydrogel exhibited AChE-positive reaction products over several hundreds of micrometers. CONCLUSIONS: These results are complementary to our previous report on electrophysiological evidence of septo-hippocampal reconnections (Duconseille et al., Rest. Neurol. Neurosci. 15, 1999, 305-317). They further suggest that septal neurons grafted homotopically and/or neurons from the host brain are able to elongate axonal processes through a PHPMA substrate up to the hippocampus. Although they did not affect the cognitive consequences of the lesion, the changes enabled by the homotopic grafts combined to the hydrogel have attenuated the lesion-induced hyperactivity.