The Roles Of Msns Excitability In NAc And LTP Induction In Hippocampus In Pathogenesis Of Depression

Depression is the most popular mental illness in the world today. InChina, there are about over26million people suffering from depression withhigh morbidity and low diagnostic rate, which causes severe impact onChina’s economic, cultural and social development. Meanwhile, thecomplex pathogenic mechanisms of depression, including genetic andenvironmental factors, and less of detectable changes in the pathologicalaspect bring great obstacles to the investigation of pathogenic mechanismsof depression and the development of antidepressant. Therefore, theclarification of the pathological mechanism, and providing effective ideasand methods for the clinical treatment are important topics and urgentscientific issues in the world’s mental illness area. Nowadays, nuclear accumbens (NAc), which responsible for the mechanism of reward andaddiction attracted more and more attentions in the field of depression andantidepressant studies. NAc, located in the basal ganglia area, areresponsible for information integration which mainly receives thedopaminergic neural projections that send from ventral tegmental area(VTA), participates in neurological circuits that relevant to the emotionregulation. Meanwhile, based on the hypothesis of pathogenesis, it wasconsidered that dopamine plays a not negligible role in pathogenesis ofdepression. However, the functions of dopamine system that regulate theactivities of neural transmission among several related brain areas are stillunclear. Therefore, it would be helpful for us to deeply understand theneuronal activity in NAc in the pathogenesis of depression, by studying thecharacteristics of neural signals. On the other hand, we also studied themutant mice which had impaired stem cell factor (SCF)/c-Kit signalingpathway in hippocampus by electrophysiology. The mutant mice exhibitsignificant depression-like behaviors and impairment of memory formationand neuronal regeneration in hippocampus. Therefore, it would be helpfulfor us to understand the effects of gene mutant on synaptic transmission andplasticity in hippocampus and the reasons for the defects of learning andmemory were analyzed. In the present study, we selected two kinds of depression model rats:Wistar Kyoto (WKY) rats and c-KitV922G/+heterozygous mutant mouse.Based on the behavioral studies,1) we studied the changes of excitability ofmedium spiny neurons (MSNs) in the pathogenesis of depression inchildhood WKY rats;2) we also studied the LTP induction in thehippocampus of adult c-KitV922G/+heterozygous mutant mice. Depending onall above studies and experiments, we discussed the characteristics of NAcMSNs’ firing pattern and the changes of synaptic plasticity in hippocampusduring the pathogenesis of depression.Main methods and results:1. The membrane excitability changes of MSNs in NAc core region inthe process of depression and its improvement in childhood WKY rats.1) Prepared coronal brain acute slices (300μM, contained NAc region)from healthy WKY and Wistar rats (4-5weeks old, male).2) Through visually guided whole-cell patch clamp recording, wecalculated the membrane excitability of MSNs in the core of NAc of WKYrats. Under the current clamp mode, the stimulation was applied to MSNs byincreasing current intensity from0pA to500pA, with50pA increment.During the process of experimental recording, picrotoxin and kynurenic acid were applied to block the inhibition GABAAreceptors and the excitatoryglutamate receptors respectively. The results showed that the inhibition ofMSNs membrane excitability by dopamine D2-like receptor-mediatedsignaling was attenuated.3) Treated childhood WKY rats with nomifensine for12day(nomifensine, a dopamine and norepinephrine reuptake inhibitor), and toexamine the depression-like behavior through open field test and forcedswimming test. Childhood WKY rats have shown significant depressivebehaviors in sucrose preference test, open field test, and forced swimmingtest, while accepted the nomifensine treatment, childhood WKY ratsexhibited decreased the depressive behaviors in sucrose preference andforced swimming test.4) Compared the membrane excitability of MSNs to control WKYrats and normal wistar rats, the excitability of MSNs in NAc core region oftreated WKY rats was suppressed.2. The formation of long-term potentiation (LTP) in Mossy fiber-CA3(MF-CA3) and Schaffer collateral-commissural fiber-CA1(Sch-CA1)pathway in c-KitV922G/+heterozygous mutant mouse.1) Prepared hippocampal acute slices (400μm) from c-KitV922G/+heterozygous mutant mouse and the wild control mouse (2~3months old, healthy, male).2) By using field potential recording technique, HFS (100Hz/1sec)twice, was delivered to MF-CA3pathway or Sch-CA1pathway respectivelyto induce LTP. At the end of experiments, ACSF containing DCG IV wasapplying to block EPSP response to verification the MF-CA3pathway. Theresults showed that LTP induction was impaired in MF-CA3but not inSch-CA1pathway in c-KitV922G/+heterozygous mutant mice.Main conclusions:1) Nomifensine treatment could improve depressive-like behavior ofWKY rat.2) The impairment of inhibition on MSNs membrane excitability whichmediated by dopamine D2-like receptor may be involved in the formation ofdepression-like behavior in childhood WKY rats.3) Nomifensine may act on WKY rats via modulation of DRD2expression in hippocampus and striatum, but not in NAc.4) The disturbed function of SCF/c-Kit pathway could inhibit the LTPinduction, which possibly participates in the impairement of learning andmemory in mutant mice.