Hippocampal Telomerase Is Involved In The Modulation Of Spatial Learning And Memory

Spatial learning and memory is such a kind of memory which is to detect spatial orientation,reaction time,visual perception and structural applications.The adult hippocampus,a crucial structure for the formation of certain types of memory,such as episodic memory and spatial memory,is one of the most plastic regions in the mammalian brain as new principal neurons are generated continuously throughout life in the dentate gyrus(DG)originating from neural progenitor cells(NPCs).The DG,which receives direct inputs from the entorhinal cortex and sends projections to the CA3 region,is traditionally considered the information gateway to the hippocampus.Upon joining DG circuits,these newly born neurons are more likely to be recruited into emerging memory traces.With high excitability and synaptic plasticity,new neurons in the DG make a unique contribution to memory processing and pattern separation.Telomere length is essential for the prolonged persistence of stem cell function in organs with extensive cell turnover.In eukaryotic cells,the synthesis and maintenance of telomere are mediated by telomerase,a specialized ribonucleoprotein with reverse transcriptase activity.Telomerase consists of an essential telomerase RNA(TERC)that serves as a template for the addition of telomere repeats,and the reverse transcriptase catalytic subunit(TERT).Telomerase activity is present at high levels in neural stem cells in the developing and adult brain.Furthermore,telomerase-deficient mice exhibit reduced proliferation but also impaired neuronal differentiation and neuritogenesis.Recently,we showed that overexpressing telomerase by intrahippocampal infusion of recombinant adenovirus vector expressing mouse TERT(Ad-mTERT-GFP)led to neurogenesis upregulation.Thus,telomerase may be involved in the procedure of adult neurogenesis and the regulation of spatial memory.So we mainly study the role of telomerase in spatial learning and memory.Here,we investigated the following three questions:(1)whether hippocampal telomerase is necessary for spatial learning and memory;(2)whether overexpression of hippocampal telomerase can improve spatial learning and memory;(3)how does hippocampal telomerase regulate spatial learning and memory.Chapterl.Hippocampal telomerase is necessary for spatial learning andmemory.TERT protein and telomerase activity existed in the adult hippocampus substantially.In order to study the relationship between the hippocampus telomerase and spatial memory,we thus examined the hippocampus-dependent spatial memory in TERT-deficient mice(TERT-/-)which expressed inactive TERT.We exposed TERT-/-and wild type TERT+/+ mice to the Morris water maze task(MWM),novel object recognition and T maze.All the results show that TERT-deficient leads to an impaired spatial memory,but has no effect on working memory.Then,we disrupt the expression of TERT by intrahippocampal infusion of LV-TERT/RNAi-GFP or AZT.The MWM task shows mice treated with LV-TERT/RNAi-GFP or AZT display a spatial cognitive impairment.So hippocampal telomerase is necessary for spatial learning and memory.Chapter2.Overexpression of hippocampal telomerase can improve spatial learning and memory.We construct a recombinant adenovirus vector expressing mouse TERT(Ad-mTERT-GFP).We overexpress TERT in TERT+/+ mice by intrahippocampal infusion of Ad-mTERT-GFP.The MWM task shows that oversxpression of TERT in normal mice significantly improve spatial learning and memory after 30 days.Then,we overexpress TERT in TERT-/-mice by intrahippocampal infusion of Ad-mTERT-GFP,which can significantly reverse spatial cognitive impairment.We have proved that chronic mild stress(CMS)led to a significant decrease in telomerase reverse transcriptase(TERT)level and telomerase activity in the hippocampus.So we inject Ad-mTERT-GFP into hippocampus before CMS.Results show that over-expression of telomerase in the hippocampus is able to reverse the CMS-induced spatial memory impairment.Chapter3.Requirement of neurogenesis for the role of telomerase in behavioral modulationFirst,we culture embryonic neurospheres from TERT-/-and WT mice.The Results show that the proliferation of embryonic NSCs in TERT-/-mice significantly decrease,and it substantially reduces neuronal differentiation,which may be due to the downregulation of Wnt/β-catenin signaling pathway.Moreover,tlomerase still exsits in immature neurons,which can promote neuronal neuritogenesis.In addition,we disrupt neurogenesis in the dentate gyrus by X-irradiation(15 Gy)of a restricted region of mouse brain containing the hippocampus.Before X-irradiation,we overexpress TERT in mice by intrahippocampal infusion of Ad-mTERT-GFP.It is showed that overexpression of telomerase are not able to reverse the spatial memory impairment by X-irradiation.These data prove that hippocampal telomerase is involved in the modulation of spatial learning and memory via newborn neurons.