Arginine Vasopressin Reversed Aβ_25-35-Induced Depression Of Hippocampal Long-Term Potentiation In Rat In Vivo

Alzheimer's disease(AD)is a primary irreversible neurodegenerative disorder characterized by progressive impairment of learning,memory and other cognitive functions, ultimately developing into mental deficiency and dementia.The main pathological characteristics of AD include the high density of senile plaques(SP)in the brain,neurofibrillary tangles(NFT)and loss of neuron in the affected brain regions.The main constituent of SP is amyloidβ-peptide(Aβ)constituted by 39-43 amino acids.At present,the neurotoxicity of Aβhas been widely reported.Therefore,the deposition of Aβin the brain and its neurotoxicity have been linked to the pathogenesis of AD,and the Aβhypothesis in AD has been accepted widely. However,the possible mechanisms by which Aβimpairs neurons are now still uncertain and there is still no effective measure in the prevention and treatment of AD.Hippocampus is one of the important structures in the central nervous system(CNS),which has been related closely to learning and memory functionally.Also,hippocampus is one of the regions where SPs accumulate in the brain of AD patients.Hippocampal Long term potentiation (LTP)is a persistent enhancement of excitatory synaptic transmission induced by preceding operations of high-frequency stimulation(HFS).The experiments with transgenic mice which highly expressed Aβin the brain show that the age dependent memory deficits are closely related to the impaired hippocampal LTP in hippocampus,which is similar to the findings in AD patients.Thus,Hippocampus LTP has long been thought to be a suitable model for not only the study of synaptic plasticity but also the elucidation of mechanisms underlying cognitive and memory disorders,such as AD.Hippocampal paired pulse facilitation(PPF)is also an enhancement in synaptic transmission,which is produced by two continual stimulations and considered to be another parameter reflecting synaptic plasticity.The mechanism of PPF is related to the neurotransmitter release from presynaptic neurons.Arginine vasopressin(AVP)is a neuropeptide involved in the endocrine regulation of the water balance and blood pressure,also plays an important role,as a central neurotransmitter,in the regulation of some central nervous functions including learning and memory.It is reported that the concentration of AVP in the brain and the blood of the AD patients decreased significantly compared with the normal,which indicates that the incidence of the AD,to a certain extent,has a relationship with the decrease of AVP level.It is reported that AVP application can improve learning and memory in aged people,which suggests that AVP may protect neurons against neurotoxicity of Aβ,and probably,AVP plays a role in the prevention and treatment of AD and improvement of memory impairment.However,Up to now,the most experiments regarding AVP mainly focused on the observation of animal behavior.The studies on the mechanisms of AVP,especially,the effects of AVP on hippocampal LTP are rarely reported or even rather controversial.In addition,although it has been shown that Aβcan impair LTP and AVP can enhance it,but whether AVP can reverse Aβ-induced LTP suppression after co-application of AVP and Aβhas not been reported up to now.Therefore,the purposes of the present study were:(1)to further clarify the effects of AVP on rat hippocampal LTP in vivo;(2) to investigate the possible protective action of AVP on Aβ-induced LTP impairment.Since the memory impairment and the dementia happened in AD are related to the degeneration of hippocampus,and the memory enhancement by AVP is also through hippocampus,we used extracellular electrophysiological technique and recorded field excitatory postsynaptic potential(fEPSP)from the Schaffer collateral/stratum radiatum of hippocampal CA1 area.We observed the effects of different concentration of AVP,Aβfragment 25-35 (Aβ_25-35),and co-application of AVP and Aβon the in vivo baseline fEPSPs,HFS-evoked LTP and PPF,and try to confirm the neuronal regulation of AVP in synapse transmission efficiency, the neurotoxicity of Aβon the synaptic plasticity,and the neuronal protection of AVP against the impairment of Aβ_25-35on hippocampal LTP.The results showed that:(1)Intracerebroventricular(i.c.v.)injection of 25nmol Aβ_25-35(in 5μL)and different concentration of AVP(0.1nmol,1nmol,10nmol)did not affect the baseline fEPSPs during 30 min of recording period.(2)In control group(n=12),HFS(three stimulus trains,20 test pulses in each train,200 Hz,30 s inter train interval)effectively evoked LTP.The amplitude of fEPSPs increased to 206±8.3%(setting the mean baseline amplitude of fEPSPs before HFS arbitrarily as 100%)immediately at the end of HFS,and the LTP still remained at 164±6.3%,and 158±7.0%,respectively,as examined 30 min,60 min after HFS.(3)After pretreatment(i.c.v.injection)with 5μL 25nmol Aβ_25-35for 30 min,HFS-induced LTP was inhibited obviously.As examined immediately,30 min and 60 min post-HFS,the LTP value significantly decreased to 160±9.5%,110±8.6%and 98±8.4%(n=6,P＜0.01),respectively,from 206±8.3%,164±6.3%and 158±7.0%in control group at the same time points(n=12).(4)After co-injection of three different concentration AVP and Aβ_25-35(25nmol),the suppressed LTP by Aβ_25-35recovered at different degree.In 0.1nmol AVP+Aβgroup,AVP produced a little recovery for the Aβ_25-35-mediated depression of LTP,but no statistical difference.The LTP value at immediately,30 min and 60 min after HFS,was 168±8.5%,115±6.4%and 106±7.1%, respectively,compared to the control group of Aβ_25-35(160±9.5%,110±8.6%and 98±8.4%, n=6,P＞0.05).In 1nmol AVP+Aβ_25-35group and 10nmol AVP+Aβ_25-35group,the LTP at three time points mentioned above are 203±9.5%,164±7.8%and 151±5.6%;204±11%,185±8.7%and 174±5.6%,respectively,showing significant differences compared to the group of Aβ_25-35alone (P＜0.01)and a dose-dependent effect.(5)After i.c.v,injection of three different concentration AVP(0.1nmol,n=7;1nmol,n=6;10nmol,n=7),the HFS-induced LTP at three time points are 198±12%,170±8.4%,156±9.1%;250±12%,192±7.8%,180±9.7%and 253±9.7%,197±7.1% and 192±8.2%,respectively,with significant difference in 1nmol and 10nmol AVP groups compared to control at the same time points(P＜0.01),but without statistical difference between this two groups and between 0.1nmol AVP and control group(P＞0.05).(6)The drugs mentioned above including AVP,Aβ_25-35,and co-application of AVP and Aβ_25-35did not affect paired stimuli-induced PPF significantly.These results indicate that:(1)0.1-10nmol AVP and 25nmol Aβ_25-35did not affect the baseline synaptic transmission.(2)Three concentration of AVP showed a dose-dependent LTP enhancement,indicating AVP can up-regulate synaptic transmission in hippocampal CA1 region. The significant enhancement of LTP by 1nmol and 10nmol AVP but without difference between both of them,in addition to no significant increase of LTP by 0.1nmol AVP,suggesting that the effective concentration of AVP in enhancing LTP may be limited in a small range,easy to reach its saturation concentration.(3)The depression of LTP induced by Aβ_25-35can be reversed by AVP in a dose-dependent manner,suggesting that AVP can counteract the neurotoxicity of Aβ_25-35and positively modulate the synaptic plasticity.(4)The PPF was not affected by AVP and Aβ,indicate that Aβ_25-35-induced depression of LTP and AVP-induced enhancement of LTP are mainly involved in the modulation of the postsynaptic processes,not the alteration of presynaptic transmitter release.