The Effects Of ApoE4 On Long-Term Potentiation In Rat Hippocampus In Vivo And Its Possible NMDAR Mechamism

Alzheimer's disease(AD),the most common form of dementia in the elderly,is a primary irreversible neurodegenerative disorder characterized by a progressive impairment of learning and memory,cognitive function and personality change,as well as neuropathological features such as the loss of neuron degeneration,senile plaques(SPs) and neurofibrillary tangles(NFTs). ApoE is found present in both SPs and NFTs,indicating that apoE is involved in the pathological processes of AD.These data prompts the association between apoE and AD-related pathology.It can be concluded that apoE is closely related to the development of AD.As one of apolipoprotein family,apolipoprotein E possesses a number of biological properties.In addition to its role in the transport of lipid particles,apoE appears to be involved in many important life processes in the central nervous system such as myelination,dendritic growth,neural remodeling and the maintenance of synaptic plasticity.In humans,three major isoforms of apoE(apoE2,apoE3,and apoE4) are encoded respectively by three allelic variants (ε2,ε3,andε4).Each genotype represents a different proportion of the population,APOEε3 is the most common allele.Increasing investigations reveal that inheritance ofε4 allele gene represents high occurrence and low age of onset of AD.It has been widely accepted that APOEε4 is a susceptibility gene especially for late-onset familial AD and sporadic AD.Hippocampal long-term potentiation(LTP),a persistent enhancement of excitatory synaptic transmission induced by high-frequency stimulation(HFS),has been accepted for the cellular basis of learning and memory.Hippocampus is the earliest and most vulnerable regions in the brain during the pathogenesis of AD.As a popular electrophysiological model about learning and memory,hippocampal LTP has been widely used to study the pathogenesis of AD.However,the results about effects of apoE isoforms on LTP in vitro were rather controversial.Some researches indicated a beneficial function of apoE on LTP,while other experiments showed a detrimental influence of apoE on LTP.Especially,it is still unclear whether and how apoE isoforms affect LTP in vivo.Increasing scientific evidence suggests that glutamate receptors-mediated neurotoxicity is involved in the pathogenesis of AD.Of three glutamate ionotropic receptor subtypes,the NMDA receptor functions more necessarily in synaptic plasticity because of its high permeability to Ca²⁺ ions.Thus,the present study examined isoform-specific effects of apoE on in vivo LTP in rat hippocampal CA1 region and the possible NMDAR mechanism by acute intracerebroventricular (i.c.v.) injection of recombinant human apoE4 and apoE3 and recording hippocampal field excitatory postsynaptic potential(fEPSP).Objective:(1) To observe the effects of apoE4 on the induction and maintenance of long-term potentiation in rat hippocampus in vivo;(2) To justify whether NMDARs are the targets of apoE.Methods:(1) Field excitatory postsynaptic potentials(fEPSPs) in the CA1 region of rat hippocampus was recorded by electrophysiological technique;(2) Recombinant human apoE was given through intracerebrovenrticular injection;(3) MK801,one of NMDA receptor antagonist,was given through intraperitoneal injection;(4) PPF was recorded immediately prior to injection of vehicle and recorded again 30 min following HFS.Results:The results showed that pretreatment with apoE4(0.5～2μg) did not affect the basal synaptic transmission,but significantly suppressed the HFS-induced LTP in a dose-dependent manner.The average amplitude of fEPSPs after application of 0.5μg apoE4 decreased significantly from 210.0±10.7%,167.7±5.9%and 165.4±5.1%in control group to 192.1±8.6%,147.7±3.9%and 145.6±3.9%respectively at 1 min,30 min and 60 min after HFS (P＜0.01);the values dropped to 172.1±2.0%,129.3±5.1%and 121.1±3.9%for 1μg apoE4 application(P＜0.001),and further decreased to 151.8±3.9%,108.0±4.3%and 103.5±3.8%in 2μg apoE4 group(P＜0.001).In contrast to apoE4,apoE3,the most common type of human apoE, had no visible effect on HFS-induced LTP compared with vehicle injection.At the same time, apoE4 did not affect paired-pulse facilitation(PPF) ratio.Further,MK801,a noncompetitive antagonist of NMDAR significantly suppressed the HFS-induced LTP in the hippocampal CA1 area in vivo when applied alone,but did not further enhance apoE4-induced LTP impairment when co-applied with apoE4.The values of fEPSP amplitude in co-application group were 146.2±2.3%,108.1±3.9%and 100.8±3.1%,showing no significant statistical difference(P＞0.05) at three time points as compared to the values(151.1±4.7%,107.5±5.1%and 101.0±2.6%) in apoE4 alone application group.Conclusion:These results suggest that apoE exerts isoform-specific effects on hippocampal LTP,with apoE4 impairing the induction of hippocampal LTP,and apoE3 maybe maintaining the induction of LTP.These findings give rise to the hypothesis that postsynaptic NMDA receptors,but not presynaptic transmitter release is involved in the suppression of LTP induced by apoE4.