Roles Of Hippocampal (Dentate Gyus) Gaba In Spatial Learning And Memory In A Rat Model Of Vascular Dementia

Vascular dementia(VD)is the second most common form of age-related neurological dysfunction after Alzheimer’s disease(AD).The core symptom of VD is progressive cognitive dysfunction due to cumulative regional brain tissue injury associated with localized cerebrovascular disruptions.Learning and memory is a foundation for cognitive function,and it is necessary index in the study of cognitive function.Hippocampus is a key structure involved in learning and memory processes,particularly in spatial learning and memory.The mammalian hippocampus is cytoarchitecturally divided into several subregions such as CA1,CA3,and the dentate gyrus(DG).As the entry point of new informations into the hippocampus,the DG encodes and processes spatial information and plays an essential role in spatial learning and memory.Although recent studies suggest the possibility that the hippocampal DG has important roles in spatial learning and memory deficits of VD,the chemical mediators in the DG responsible for the spatial learning and memory deficits of VD are incompletely understood.y-aminobutyric acid(GABA)has been recognized as an important inhibitory neurotransmitter in the central nervous system.It has been shown that there are a lot of GABAergic neurons in the hippocampal DG region,and GABAA and GABAB receptors in the DG regulate synaptic plasticity as well as learning and memory processes.However,the roles of the GABA and its receptors in the DG in spatial learning and memory impairments of VD have not been reported.Therefore,in the present study,we established a rat model of VD by permanent bilateral carotid occlusion(2-VO),and have used microdialysis,high performance liquid chromatography(HPLC),immunohistochemical staining,microinjection and Morris water maze(MWM)methods to study the effect and mechanism of GABA in the hippocampal DG on spatial learning and memory impairment of VD.Five parts of experiment were carried out:1.VD model rats prepared with 2-VO,and then 1)spatial learning and memory abilities of rats were assessed by MWM;2)the extracellular concentrations of GABA in the DG were examined by in vivo microdialysis and HPLC methods;3)the expressions of GABAA and GABAB receptors in the DG were measured by immunohistochemistry.2.The effects of microinjection of bicuculline(an antagonist of GABAA receptors)and saclofen(an antagonist of GABAB receptors)into the DG in the spatial learning and memory in VD rats were demonstrated.3.The bicuculline and saclofen were microinjected into the hippocampal DG,and the extracellular concentrations of amino acids in the DG,including aspirate(Asp),glutamate(Glu),glutamine(Gin),glycin(Gly)and taurine(Tau),were measured in VD rats during MWM test.4.The changes of GABA in the DG were measured in normal rats during MWM test.5.The effects of microinjection of muscimol(an agonist of GABAA receptors)and baclofen(an agonist of GABAB receptors)into the DG in the spatial learning and memory in normal rats were demonstrated.The experimental results are as follows:1.In the place navigation trail,the escape latency was decreased with the increase in training days in both groups,but the mean escape latency was significantly longer in VD group than sham-operated group;in the spatial probe trail,the number of platform crossings was markedly lessened in VD group compared with the sham-operated group.2.Compared with the sham-operated group,the extracellular concentration of GABA in hippocampal DG was significantly increased in the VD model group.3.The number of GABAB receptor-positive cells in the DG in VD model group was decreased compared to the sham-operated group,whereas the number of GABAa receptor-positive cells in the DG did not changed.4.The microinjection of bicuculline into the DG did not affect the escape latency and the number of platform crossings of VD rats in MWM test.5.The microinjection of saclofen into the DG elicited a significant decrease in escape latency and a significant increase in number of platform crossings in VD rats during MWM test.6.In sham-operated group,the extracellular concentrations of Glu,Gin and Gly in the DG were significantly increased during MWM test,and the increases were attenuated in VD model rats.7.The microinjection of bicuculline into the DG did not affect the extracellular concentrations of Glu,Gin and Gly in the DG during MWM test.8.The microinjection of saclofen into the DG partly reversed the inhibitory effects of VD in changes of Glu,Gin and Gly in the DG during MWM test.9.The extracellular concentrations of GABA in the DG were decreased with the increase in training days in normal rats.10.The microinjection of muscimol or baclofen into the DG induced a significant increase in mean escape latency and a significant decrease in number of platform crossings in normal rats during MWM test.Conclusions1.Spatial learning and memory impairment of VD model rats is related to increase in GABA concentrations in the hippocampal DG2.The increase in GABA of the DG in VD rats involves in spatial learning and memory impairment mainly via GABAb receptors.3.Glu,Gin and Gly in the hippocampal DG were involved in the spatial learning and memory process,and activation of GABAB receptors in the DG induces spatial learning and memory impairment in VD rats by means of inhibition of the changes in these amino acids during MWM test.