Disturbance Of Hippocampal CaMK? Signal Participate In Pathological Process Of Autism

Autism spectrum disorders(ASDs)are a heterogeneous group of bio-neurological developmental disorders that display common behavioral symptoms,including pervasive impairments in social interactions.With the deepening of autism research,it has been gradually realized that autism is a kind of diffuse central nervous system dysplasia caused by multiple environmental factors.Based on this understanding,carrying out the research from molecular genetics to neural immune,functional imaging,nerve anatomy and neurochemical etc.Up to now,its etiology and pathogenesis have not been elucidated.Synaptic alterations underlie the abnormal social and cognitive behaviors that are observed in humans with ASDs.However,little is known regarding the role of hippocampal protein serine/threonine kinases during the pathological process of ASD.CaMK? is highly enriched in the postsynaptic densities of excitatory synapses and remains constitutively active via autophosphorylation at threonine-286,which facilitates synaptic efficacy.In addition,PKC isoforms phosphorylate the NMDA receptor,which is required to enhance CaMK?-dependent long-term potentiation(LTP).Some studies have suggested an increased prevalence of developmental delays and cognitive dysfunctions in children who have been exposed to anticonvulsant drugs in utero.Moreover,these studies have indicated that alterations in NMDA tone may be responsible for the excessive self-grooming observed in an animal model of ASD.However,the precise intracellular biochemical basis underlying ASD-mediated cognitive deficits has not been fully elucidated.Objective:This study aimed to evaluate the effects of chronic melatonin treatment on disturbances of the serine/threonine kinases signaling system,synaptic efficacy and autism-like social behavioral disorders.Methods:VPA autism rats were used and different doses of melatonin were administrated for four weeks.Experimental changes in the phosphorylation of CaMK? proteins were determined by immunoblotting and immunohistochemistry.Results:Compared with the control group,we observed a dramatic decrease in CaMK?(Thr286)phosphorylation in the hippocampal region of VPA-treated rats at PND50.In the present study,a significant decrease in synapsin I(Ser603)and GluR1(Ser831)phosphorylation was observed in the hippocampi of VPA-treated rats,suggesting that the dephosphorylation of CaMK?/synapsin I/GluRl in the hippocampus may be associated with the pathological processes of ASD.To understand whether the restoration of CaMK?/PKC/PKA phosphorylation by melatonin treatment correlated with changes in memory formation,the hippocampal LTP in the CAl region of VPA-treated rats was recorded.Here,markedly reduced LTP was observed in vehicle-treated VPA rats(139.3 ± 2.6%of baseline during 1-5 min;116.3 ± 2.4%of the baseline during 26-30 min;113.2 ± 2.3%of the baseline during 56-60 min,n = 5).Melatonin(5 mg/kg)treatment significantly improved LTP in hippocampal CAl regions(151.3 ± 3.7%of the baseline during 1-5 min;135.7 ± 3.6%of the baseline during 26-30 min;133.4 ± 3.9%of the baseline during 56-60 min,n =5),whereas no significant changes were observed 1-5 min after HFS compared with VPA-treated rats.We used a social interaction test to investigate whether melatonin improved the dysfunctional social behaviors observed in VPA-treated rats.Here,VPA-treated rats exhibited a significant decrease in social interaction behaviors compared with control rats.In addition,VPA-treated rats were tested after chronic treatment with melatonin for four weeks(1 or 5 mg/kg,p.o.)using an automated three-chambered social approach apparatus.Interestingly,the melatonin-treated rats showed a significant rescue of the VPA-induced impairment of social interaction behavior.Moreover,melatonin treatment increased the time spent in proximity to and the frequency of reciprocal social interactions with a social partner compared with vehicle-infused VPA-treated rats.Conclusions:The present results indicate that disruptions in hippocampal CaMK?/PKA/PKC signaling have been observed in VPA rats.Importantly,melatonin significantly prevented hypo-phosphorylation of serine/threonine kinases signaling as well as decreasing of LTP in the hippocampus observed in an ASD model.We suggested that restoration of CaMK?/PKC/PKA phosphorylation and LTP formation induction by melatonin might correlate with ameliorated dysfunction of social behavior seen in the VPA-treated rats.