Dynamic Expression Of Glutamate Receptor Of Hippocampus, Prefrontal Cortex And Amygdala In An Animal Model Of PTSD

Post-traumatic stress disorder (PTSD) is a debilitating anxiety disorder that may develop after an individual has experienced or witnessed a severe traumatic event. It has been know over a hundrand years, ever been named as "shell shock"or "war neurosis". PTSD is characterized in the DSM-III by a phenomenological triad incorporating the symptoms of re-experiencing, avoidance and hyperarousal. The re-experiencing symptoms of PTSD include nightmares, intrusive memories and flashbacks of the trauma. The avoidance symptoms Neurobiology of posttraumatic stress disorder include amnesia for the trauma or a reluctance to discuss or think about the trauma. Finally, the hyperarousal symptoms include an exaggerated startle response, fitful sleep and poor concentration.Most functional brain imaging studies in PTSD have used either PET or fMRI. Imaging studies in PTSD patients have demonstrated volume reductions in the hippocampus that appear correlated with illness severity and the degree of cognitive deficit, although there is evidence of decreased hippocampal volume predating PTSD. PTSD subjects also showed a small but significant enhancement in left amygdala activity, most apparent during the late phase, but reduction in Early right amygdala response. In contrast, prefrontal cortex appears to be volumetrically smaller and is hyporesponsive during symptomatic states and the performance ofcognitive tasks in PTSD.Glutamate receptors are classified into two groups: ionotropic and metabotropic receptor families. There are three major types of ionotropic glutamate receptors (iGluRs), which are named after reasonably selective agonists, thus, called N-methyl-D-aspartate (NMDA), α-amino-3-hydroxy-5-methyl-4-isoazolepropionic acid (AMPA) and 2-carboxy-3-carboxymethyl-4-isopropenylpyrrolidine (kainate) receptors. Ionotropic glutamate receptors mediate the vast majority of fast excitatory synaptic transmission in the CNS. NMDA receptors are heteromeric complexes incorporating different subunits within a repertoire of three subtypes: NR1, NR2 and NR3. It is widely recognized that the NR1 subunit is essential to the functional NMDA receptor channels, while various combinations of NR2 and NR1 subunits could endow NMDA receptor channel with different functional properties. NMDA receptor is a voltage-dependent ligand-gated ion channel. Activation of NMDA receptor not only requires to bind with glutamate and glycine, but also need to remove Mg²⁺ from NMDA receptor channel by membrane depolarization. AMPA receptors can exist as either homomeric or heteromeric assemblies of GluR1-4 receptor. AMPA receptors are the principal molecular units for fast excitatory synaptic transmission in the central nervous system. Activation AMPA receptor cause local membrane depolarization, which can release Mg²⁺ from nearby NMDA channel. Previous studies indicated, activation of NMDA receptor can induce AMPA receptors to insert into cell membrane of dendrite spine and enhance the synapse transmission efficiency.Until now, there is no wonder drug which can be used for PTSD medications and other mental disorder is always clinically used instead. Pevious pharmacological studies indicated that inhibition of AMPA receptor can ameliorate the symptom of PTSD, whereas the brain regions and mechanisms which are involved in PTSD are unknown. According to brain imaging studies, the brain regions involved in PTSD may include hippocampus, prefrontal cortex and amygdala, which may change functionally and structurally. It is well known that glutamate receptors play a key role in synaptic plasticity. In additon, PTSD is associated with fear memory andsynaptic plasticity in these brain regions. Therefore, in this study, to explore the sensitization mechanism of PTSD, we examined the expression level of the glutamate receptors in the hippocampus, prefrontal cortex and amylgada regions of PTSD model. It may aid to understand the underlying mechanism of PTSD sensitization and provide value for clinical therapy.So far, there is no any animal model of PTSD which can mimic human symptom. According to Rau V's study, we established an animal model of PTSD, which successfully mimic the sensitizaiton, one of the important symptoms of PTSD. Exposure therapy (extinction) and amnestic (NMDA antagonist) treatment have no effect on this PTSD model. After treatment described as above, animals were sacrificed immediately. Hippocampus, prefrontal cortex and amygdala were dissected on ice. Total protein and membrane protein extraction were carried out using techniques described previously. Then, we examined the expression of NR1 and GluRl by Semi-quantitative Western blotting analysis. We found that hippocampal GluRl in membrane fraciton of PTSD group increased and maintained at hight level compared with control group. It suggests that trauma event may effect on synaptic structure and founction in hippocampus, thus result in behavioral sensitization. Moreover, our results indicate that, in stress groups, expression of NR1 and GluRl decreased compared with Naive group, which suggests stress reduced activity, and is consistent with neruoimaging. Finaly, NR1 amygdaloid totl lysis of PTSD group is increased. It suggests that NR1 increase may be related with fear memory of PTSD.