Primary CA1 and conditionally immortal MHP36 cell grafts restore conditional discrimination learning and recall in marmosets after excitotoxic lesions of the hippocampal CA1 field

Common marmosets (Callithrix jacchus, n = 18) were trained to discriminate between rewarded and non-rewarded objects (simple discriminations, SDs) and to make conditional discriminations (CDs) when presented sequentially with two different pairs of identical objects signifying reward either in the r ight or left food well of the Wisconsin General Test Apparatus. After bilat eral N-methyl-D-aspartate (0.12 M) lesions through the cornu ammonis-1 (CA1 ) field (7 mu l in five sites), marmosets showed profound impairment in rec all of CDs but not SDs, and were assigned to lesion only, lesion plus CA1 g rafts and lesion plus Maudsley hippocampal cell line, clone 36 (MHP36) graf ts groups matched for lesion-induced impairment. Cell suspension grafts (4 mu l, 15-25 000 cells/mu l) of cells dissected from the CA1 region of foeta l brain at embryonic day 94-96, or of conditionally immortalized MHP36 cell s, derived from the H-2K(b)-tsA58 transgenic mouse neuroepithelium and labe lled with [H-3]thymidine, were infused at the lesion sites. The lesion plus MHP36 grafts group was injected five times per week with cyclosporin A (10 mg/kg) throughout testing. Lesion, grafted and intact control marmosets ( = 4-5/group) were tested on recall of SDs and CDs learned before lesioning and on acquisition of four new CDs over a 6-month period. Lesioned animals were highly impaired in recall and acquisition of CD tasks, but recall of S Ds was not significantly disrupted. Both grafted groups of marmosets showed improvement to control level in recall of CDs. They were significantly slo wer in learning the first new CD task, but mastered the remaining tasks as efficiently as controls and were substantially superior to the lesion-only group. Visualized by Nissl staining, foetal grafts formed clumps of pyramid al-like cells within the denervated CA1 held, or jutted into the lateral ve ntricles. MHP36 cells, identified by beta-galactosidase staining and autora diography, showed neuronal and astrocytic morphology, and were distributed evenly throughout the CA1 region, The results indicate that MHP36 cell graf ts are as functionally effective as foetal grafts and appear to integrate i nto the host brain in a structurally appropriate manner, showing the capaci ty to differentiate into both mature neurons and glia, and to develop morph ologies appropriate to the site of migration. These findings, which paralle l the facilitative effects of foetal and MHP36 grafts in rats with ischaemi c CA1 damage, offer encouragement for the development of conditionally immo rtal neuroepithelial stem cell lines for grafting in conditions of severe a mnesia and hippocampal damage following recovery from cardiac arrest or oth er global ischaemic episodes.