The effects of NGF and fetal cell transplants on spatial learning after intradentate administration of colchicine

Abstract

This study was performed to assess the effects of NGF infusion alone or in combination with fetal hippocampal transplants on recovery of function after damage to hippocampal dentate granule cells. Two groups of male Fischer-344 rats received bilateral infusions of colchicine (COLCH; 2.5 micrograms/site) or artificial cerebrospinal fluid (ACSF; 0.5 microliter) through chronic indwelling cannulae into the dentate gyrus. At the time of COLCH injection, a unilateral intracerebroventricular (ICV) cannula was implanted. One week later, when animals were tested in activity chambers for 60 min, COLCH-treated rats showed a significant increase in spontaneous locomotor activity. Two weeks after COLCH treatment, animals were assigned to various post-treatment groups and received 1.0 microliter of rat fetal hippocampal cell suspensions (ED-17 or 18) or Earle's basic salt solution in the same site as previous hippocampal infusions. Modified Alzet miniosmotic pumps (0.25 microliter/h) containing NGF (10 ng/microliter) or ACSF with cytochrome C (20 ng/microliter) were implanted subcutaneously and attached to the previously implanted ICV cannulae. The animals were tested for learning ability in a Morris water maze task starting 6 or 12 weeks post-COLCH. During both test periods, COLCH lesions significantly impaired acquisition and retention. At 6 weeks postlesion, NGF treatment ameliorated this COLCH-induced behavioral deficit while the presence of transplants did not ameliorate the COLCH-induced learning deficit. COLCH/transplant/NGF-treated rats performed better than both COLCH-lesioned rats with or without transplants. At 12 weeks postlesion COLCH-induced behavioral deficits were not ameliorated by NGF or transplants. Morphological examination performed after behavioral testing confirmed the presence of viable transplants and COLCH-induced granule cell loss. Exogenous NGF infusions appeared to have no effect on the morphological measures taken. These data demonstrate a time-dependent facilitative effect of exogenously applied NGF on functional deficiencies produced by experimentally induced neurodegeneration in the dentate gyrus of the hippocampus.