Selective immunolesion of cholinergic neurons leads to long-term changes in 5-HT2A receptor levels in hippocampus and frontal cortex.

Although loss of cholinergic neurons in the basal forebrain is considered a key initial feature in Alzheimer's disease (AD), changes in other transmitter systems, including serotonin and 5-HT(2A) receptors, are also associated with early AD. The aim of this study was to investigate whether elimination of the cholinergic neurons in the basal forebrain directly affects 5-HT(2A) receptor levels. For this purpose intraventricular injection of the selective immunotoxin 192 IgG-Saporin was given to rats in doses of either 2.5 or 5 microg. The rats were sacrificed after 1, 2, 4 and 20 weeks. 5-HT(2A) protein levels were determined by western techniques in frontal cortex and hippocampus. A significant 70% downregulation in frontal cortex and a 100% upregulation in hippocampus of 5-HT(2A) receptor levels were observed 20 weeks after the cholinergic lesion when using the highest dose of 192 IgG-Saporin. Our results show that cholinergic deafferentation leads to decreased frontal cortex and increased hippocampal 5-HT(2A) receptor levels. This is probably a consequence of the interaction between the serotonergic and the cholinergic system that may vary depending on the brain region.

Sulindac improves memory and increases NMDA receptor subunits in aged Fischer 344 rats.

Inflammatory processes in the central nervous system are thought to contribute to Alzheimer's disease (AD). Chronic administration of nonsteroidal anti-inflammatory drugs (NSAIDs) decreases the incidence of Alzheimer's disease. There are very few studies, however, on the cognitive impact of chronic NSAID administration. The N-methyl-d-aspartate (NMDA) receptor is implicated in learning and memory, and age-related decreases in the NMDA NR2B subunit correlate with memory deficits. Sulindac, an NSAID that is a nonselective cyclooxygenase (COX) inhibitor was chronically administered to aged Fischer 344 rats for 2 months. Sulindac, but not its non-COX active metabolite, attenuated age-related deficits in learning and memory as assessed in the radial arm water maze and contextual fear conditioning tasks. Sulindac treatment also attenuated an age-related decrease in the NR1 and NR2B NMDA receptor subunits and prevented an age-related increase in the pro-inflammatory cytokine, interleukin 1beta (IL-1beta), in the hippocampus. These findings support the inflammation hypothesis of aging and have important implications for potential cognitive enhancing effects of NSAIDs in the elderly.

Age-related working memory impairment is correlated with increases in the L-type calcium channel protein alpha1D (Cav1.3) in area CA1 of the hippocampus and both are ameliorated by chronic nimodipine treatment.

The hippocampus is critical for spatial memory formation in rodents. Calcium currents through L-type voltage-sensitive calcium channels (L-VSCCs) are increased in CA1 neurons of the hippocampus of aged rats. We have recently shown that expression of the calcium conducting L-VSCC subunit alpha(1D) (Ca(v)1.3) is selectively increased in area CA1 of aged rats. We and others have speculated that excessive Ca(2+) influx through L-VSCC may be detrimental to memory formation. Therefore, we investigated the relationship between age-related working memory decline and alpha(1D) protein expression in the hippocampus. In addition, we studied the effects of chronic treatment with the L-VSCC antagonist nimodipine (NIM) on age-related working memory deficits and alpha(1D) expression in the hippocampus. Here we report that age-related increases in alpha(1D) expression in area CA1 correlate with working memory impairment in Fischer 344 rats. Furthermore, we demonstrate that chronic NIM treatment ameliorates age-related working memory deficits and reduces expression of alpha(1D) protein in the hippocampus. The present results suggest that L-VSCCs participate in processes underlying memory formation and that increases in L-VSCC protein and currents observed with aging may play a role in age-related memory decline. Furthermore, the amelioration in age-related memory decline produced by NIM treatment may be mediated, at least in part, by reductions in the abnormally high levels of alpha(1D) protein in the aged hippocampus. These findings may have implications for patients with Alzheimer's disease, who show increased L-VSCC protein expression in the hippocampus, and for patients receiving chronic treatment with L-VSCC antagonists.

Regionally selective alterations in expression of the alpha(1D) subunit (Ca(v)1.3) of L-type calcium channels in the hippocampus of aged rats.

Calcium currents through the L-type voltage-sensitive calcium channel (L-VSCC) are increased in neurons of area CA1 of the hippocampus in aged rats and rabbits. Furthermore, increases in mRNA for the pore forming subunit alpha(1D) (Ca(v)1.3) have been observed in the hippocampus of aged rats. We have studied the protein expression of the two pore forming subunits, alpha(1C) (Ca(v)1.2) and alpha(1D), of L-VSCCs in the hippocampus of young and aged rats. Here we report selective age-related changes in expression of alpha(1D) in the hippocampus. Specifically, we find that alpha(1D) protein is increased in area CA1 of aged rats while it is decreased in area CA3. Our data suggest that the altered calcium currents seen in aged animals may be due, at least in part, to alterations in the expression of the alpha(1D) subunit of the L-type calcium channel. These findings contribute to our understanding of the mechanisms responsible for changes in calcium homeostasis during aging.

Xenografts of MHC-deficient mouse embryonic mesencephalon improve behavioral recovery in hemiparkinsonian rats.

The limited availability of human embryonic tissue for dopamine cell transplants in Parkinson's patients has led to an increased interest in using xenogeneic donor tissue. Unfortunately, without aggressive immunosuppression, such brain xenografts are rejected by the host immune system. Chronic brain xenograft rejection is largely mediated by helper T cells, which require presentation of xenoantigens by major histocompatability complex (MHC) class II for their activation. We examined survival and function of xenografts of E13 mouse mesencephalon deficient in either MHC class I, class II, or both after transplantation into adult hemiparkinsonian rats without immunosuppression. Recipients received grafts from C57BL/6 mice that were either: 1) wild-type (wt), 2) MHC class I knockout (KO), 3) MHC class II KO, 4) MHC class I and II double KO, or 5) saline sham transplants. At 6 weeks after transplantation, recipients of MHC class I KO, class II KO, and double KO xenografts significantly reduced methamphetamine-induced circling rate while rats with wt xenografts and sham-operated rats showed no improvement. MHC class II KO grafts had the greatest number of surviving dopamine neurons. All transplants, including saline sham controls, contained infiltrating host MHC class II-positive cells. Saline sham grafts and MHC class II KO xenografts contained significantly fewer infiltrating host MHC class II-positive cells than did wt grafts. Our results show that MHC class II-deficient xenografts survive transplantation for at least 6 weeks in the absence of immunosuppression, reduce rotational asymmetry, and provoke lesser immune reaction than wt grafts.