The Role Of Astrocytes And FEZ1 In Mental Disorders Induced By Frontal Lobe Injury

Mental disorders induced by frontal lobe injury are devastating mental illness with a high economic burden. Neuroimaging and neuropathological studies demonstrate prominent astroglial asthenia and astroglial atrophy occurring in most of neuropsychiatric illnesses. What’s more important is that these diseases usually accompany by frontal lobe lesions. Fasciculation and elongation protein zeta-1(FEZ1) participates in central nervous system development of mammal animals and is involved in axonal outgrowth, fasciculation and elongation. FEZ1 is one of the first identified binding partners of DISC1. FEZ1 knockout mice exhibit hyperactivity and enhanced responsiveness to psychostimulants, supporting a potential contribution of FEZ1 dysfunction to mental illness. In this study, we have evaluated the changes of rat behavior and astrocytic key markers after frontal lobe injury, and FEZ1 expression and localization in the frontal lobe, striatum and hippocampus of this model. Then we further investigated the roles of astrocytes and FEZ1 in psychopathology induced by frontal lobe injury.Objective: The aim of this research is to establish a rat model of frontal lobe injury, to explore the effects of frontal lobe injury on rats behavior. Then detected the expression of astrocytic markers GFAP and ALDH1L1 in rat frontal cortex, striatum and hippocampus, and the localization of FEZ1, CX43 in frontal cortex after frontal cortex injury, to explore the role of astrocyte and its FEZ1 in mental disorder rats induced by frontal lobe injury.Methods: Male Sprague-Dawley rats were randomly divided into two groups: frontal lobe injury group and sham group. The frontal lobe injury rat model was established by stereotaxic and blade cutting method. We applied sucrose preference test to detect sucrose preference changes of rats after frontal lobe injury, and forced swimming test to detect cumulative immobility time and the times of struggle for 4 min in rats after frontal lobe injury. Western blot was used to detect the expression of astrocytic markers GFAP and ALDH1L1, and astrocytic gap junction protein connexin43(CX43), FEZ1 in rats after frontal lobe injury at different time points(1w, 2w, 3w, 4w, 5w after frontal lobe injury). Immunofluorescent detection was applied to observe FEZ1 and CX43 expression and cellular localization in frontal lobe of rats.Results:(1)The behavioral data showed that sucrose preference significant decreased at 2 weeks after frontal lobe injury, which indicated that rats become anhedonia after frontal lobe injury. Depressive-like behavior can be reflected by forced swimming test. In this test, there were no significant differences in each cumulative immobility time, but immobility time after injury became increasing gradually and struggling times decreased significantly.(2) After injury, the expression of GFAP in the frontal cortex, striatum, hippocampus showed increase at first and then decrease, but the expression of GFAP increased significantly compared with sham group. After frontal injury, ALDH1L1 showed decline trendency and decreased significantly at 4 weeks after injury. The expression of FEZ1 was significantly decreased in frontal cortex, striatum and hippocampus, lower than that in sham group, and increased gradually after frontal lobe injury. The expression of CX43 in rat frontal cortex was significantly decreased compared with sham group, and increased gradually after frontal lobe injury, consistent with the expression of FEZ1. In striatum and hippocampus, CX43 decreased firstly and then increased after injury, reached the peak at 4 weeks, then decreased.(3) Immunofluorescence staining showed that astrocytes migrate to the injured area and mainly concentrated in the injured area. In the frontal cortex of rats, the expression of CX43 was decreased significantly, and mainly expressed in the injured area. Gradually with the passage of time the expression of CX43 increased. FEZ1 was mainly expressed in neurons in sham group and frontal lobe lesion at 1 week, while FEZ1 was mainly expressed in astrocytes at 2 and 3 weeks after injury.Conclusions: Behavior tests showed that frontal lobe injury induced rat mental disorders such as anhedonia and behavioral despair. The expression of astrocytic GFAP, ALDH1L1, CX43 and FEZ1 changes suggested that, the number of astrocytes reduce and lots of astrocytes transforme into reactive astrocytes after frontal cortex injury in rats frontal cortex, striatum and hippocampus. In frontal cortex, astrocytes migrated to site of injury and formated new gap junctions between astrocytes to participate in nerve repairment. Astrocytic gap junctions dysfunction may be the main cause of rat mental disorder induced by frontal lobe injured. The expression and localization of FEZ1 changes indicated that FEZ1 plays an important role in neuroprotection in the process of mental disorders, suggesting that astrocytes and FEZ1 play an important role in mental disorders induced by frontal lobe injury.