Role Of FGF2in Astrocytes And Synaptic Plasticity In Animal Model Of Posttraumatic Stress Disorder

【Background】Posttraumatic stress disorder (PTSD) is characterized by traumatic memories orexperiences, and increased persistent arousal which caused by the serious catastrophicincident or threat such as war and natural disaster. As emerging studies have focused onthe critical role of astrocytes in the pathological mood disorders, the underlying cellularmechanisms are not fully explained. Previous studies have confirmed that FGF2may be anovel anxiolytic molecule, but it remains unknown that the FGF2could alleviate thePTSD symptoms.【Aims】In the present study, by using the single prolonged stress (SPS) rats as a PTSD animalmodel, combined methods including behavioral testing, molecular neurobiology andmorphology, we investigated the underlying mechanisms of astrocytes invloved in theincidence of PTSD, and the effects of FGF2on synaptic plasticity in hippocampus and itspossible therapeutic mechanisms.【Methods】 (1) Establishment of single prolonged stress (SPS) rats as a PTSD animal model;(2)The level of anxiety behavior were measured by the open field test and elevated plus mazetest;(3) By using the GFAP as the indicator of astrocyte action, immunofluorescenthistochemistry was used to detect the expressions of astrocytic GFAP and NeuN inhippocampus and anterior cingulated cortex;(4) Double immunofluorescent Western blotwas performed to observe the change of astrocytic GFAP and specific neuron biomarkerNeuN in hippocampus and anterior cingulated cortex;(5) Morris water maze testwasperformed to test the change of learn and memory in the SPS rats with or without FGF2administration;(6) Conditioned fear response test was performed to test the change ofconditioned fear memory in the SPS rats with or without FGF2administration;(7) Byusing the advanced international Static Field Structure with bright vision lighting test andthree dimensional Golgi imaging and analyzing method, we observed the distribution ofdendrites and detailed changes in hippocampus in the SPS rats with or without FGF2administration;(8) DiI staining method was performed to test the density of spines with3D analyzing method and detailed changes in hippocampus in the SPS rats with or withoutFGF2administration;(9) ELISA method was performed to observe the changes of serumFGF2, cortisol, BDNF,5-HT, DA and NE in the SPS rats with or without FGF2administration;【Results】(1) Behavioral data showed that the SPS rats exhibited significant anxiety behavior,increased conditioned fear response and dysfunction of learn and memory;(2) astrocyticGFAP is significantly downregulated in SPS rats in the hippocampus and ACC, while theneuron specific biomarker NeuN was not changed during the SPS procedures;(3) Theserum level of FGF2, cortisol, BDNF,5-HT, DA and NE were significantly decreased inSPS rats compared to the control group, and these moleculars in the serum weresignificantly increased compared to the SPS group after the FGF2administration;(4)Intraperitoneal injection of FGF2could significantly alleviate the anxiety-like behaviorand conditioned fear response, and enhance the ability of learn and memory;(5) Thedendritic branching density, mean dendritic length and diameter were significantly decreased compared to the control group, and spine density, mean spines area and volumewere decreased too, but the FGF2administration could reverse the dendritic shrinkage andincrease the spine density compared to the SPS group;(6) the astrocytic action in thehippocampus and ACC is significantly enhanced after intraperitoneal FGF2administration.【Conclusion】(1)Following SPS, the expression of astrocytic GFAP is closely related withdevelopment of posttraumatic stress disorders.(2) We suggest that high doseage of intraperitoneal FGF2could block SPS-inducedconditioned fear response and anxiety-like behavior in the posttraumatic stress disordersvia enhancement of astrocytic GFAP expression but not the neuron, it was suggested thatthe FGF2application may be the novel theraputic drug for PTSD.(3) The decreased serum level of FGF2, cortisol, BDNF,5-HT, DA and NE in SPSrats were accompanyed with the anxiety symptoms, indicated that the anxiety in the PTSDpatients may be closely related with downregulation of these molecules.(4) The dendritic shrinkage and decreased spines density in hippocampus in the SPSrats may be related with the decline of the ability of learn and memory. The ability tochange the synaptic plasticity after peripheral FGF2administration may be correlated withthe alleviation of PTSD symptoms.