The Role And Underlying Mechanism Of The Stability Of Surface AMPAreceptors In Conditioned Fear Memory Of Rats

Part IThe role and underlying mechanism of the stability of surface AMPA receptors in aging-related emotional memory deficitsObjective:To study the differential expression of emotional memory, surface expression of AMPARs between adult and aged rats.Whether restore the surface expression of AMPARs is able to reverse aging-related emotional memory deficits.Methods:To study the expression of emotional memory by fear conditioning test, to identify the level of norepinephrine in hippocampus by microdialysis and high-performance liquidchromatography, to detect protein expression by western blot,electrophysiological recording was used to record LTP. Adenovirus infection and overexpression were used to affect the expression and function of GluAl. The effects of desipramine were evaluated by systematic or CA1injection.Results:(1) The learning ability in contextual fear conditioning and hippocampal LTP were impaired in aged rats(adult:81.74+4.51%, aged:46.84+5.61%; F(1,15)=23.89, P＜0.001), the surface expression of GluAl (adult:1.75+0.11,aged:1.27+0.07; F=27.60, P＜0.001) and hippocampal NE levels(adult:229.17+12.22%, aged:160.45+19.79%; F=9.240, P=0.009,20min)(adult:229.17+12.22%,aged:160.45+19.79%; F=9.240, P=0.009,40min) were reduced during contextual fear conditioning in aged rats.(2) NE treatment increased the amplitude of hippocampal LTP in aged rats(aged:106.63+4.49%, aged+10μM NE:143.76+4.03%, aged+20μM NE:177.53+9.91%; F(2,27)=30.2, P＜0.001).(3) NE treatment rescued LTP impairment via facilitating surface delivery of GluAl in aged rats(F (5,30)=3.89, P=0.008).(4) Down-regulation of NE level impaired LTP in hippocampal CA1region of adult rats.(5) Acute administration of NE or desipramine (F3,28)=7.85, P=0.001) rescued aging-related deficits emotional memory.Conclusion:The stability of surface AMPARs play an important role in the development of the impairment of synaptic plasticity and associative fear memory during aging. And desipramine may represent a brilliant drug for the treatment of aging-related deficit of emotional memory. Part Ⅱ The role and underlying mechanism of the stability of surface AMPA receptors in fear retentionObjective:To demonstrate that the surface expression of AMPA receptors is involved in retrieval and propranolol prevents fear retention in a retrieval dependent manner via modulating the stability of surface GluAl in the lateral amygdala.Methods:To study the PTSD-like behavior by fear conditioning test, to identify the level of norepinephrine in amygdala by microdialysis and high-performance liquidchromatography, to detect protein expression by western blot,electrophysiological recording was used to record LTP and EPSC. Adenovirus infection and overexpression were used to affect the expression and function of GluAl. The effects of propranolol were verified by amygdala injection.Results:(1) Propranolol attenuated fear retention and lateral amygdala-LTD in a retrieval dependent manner(F(2,21)=10.90, P=0.001).(2) Exogenous norepinephrine impairedlateral amygdala-LTD (F(3)33)=27.33, P＜O.001) and increased the surface expression of GluAl.(3) Propranolol prevented norepinephrine-induced carboxyl terminal phosphorylation and surface expression of GluAl (F(5,36)=5.77, P=0.001) in lateral amygdala.(4) Propranolol suppressed epinephrine-induced lateral amygdala-LTD impairment (P=0.53) and GluAl surface trafficking (F(6,35)=4.78,P=0.001) via its central action.(5) Propranolol (F(1.14)=78.10, P＜O.001) and overexpression of GluAl-C-tail (F(1,15)=95.72,P<0.001) both attenuatedretrieval-induced lateral amygdala-LTD impairment and fear memory retention.Conclusion:Propranolol prevents fear retention in a retrieval dependent manner via modulating the stability of surface GluAl in the lateral amygdala.