DISC1 L100P Point Mutant Mice Identify Cells And Loop Mechanisms Of Memory Impairment

Major neuropsychiatric illnesses such as schizophrenia,bipolar disorder,major depression and autism spectrum disorder are genetically complex but share not only overlapping symptoms?for example,cognition deficits in learning,memory and attention?and environmental risk factors?for example,influenza,trauma and stress?,but also molecular etiology.Disrupted-in-schizophrenia 1?DISC1?is a promising candidate susceptibility gene for a spectrum of psychiatric illnesses that share cognitive impairments in common,including schizophrenia,bipolar disorder and major depression.DISC1 was originally discovered in a large Scottish pedigree showing a heavy burden of major psychiatric disorders associated with balanced chromosomal translocation?1:11??q42.1:q14.3?.There is broad agreement that studying rare,highly penetrant risk mutations,for example DISC1,in animal models can not only shed light on the neural integrity of DISC1 and its relevance to neuropsychiatric disorders,but also help to decipher gene-environment interactions in those illnesses.Therefore,in this study,we further analyzed the cognitive and affective behaviors of L100 P mutation homozygotes and their WT littermates,and explored the underlying synaptic mechanisms as well.1.DISC1 L100 P homozygous mutant shows normal anxiety-and depression-like behavior.2.DISC1 L100 P homozygousmutant shows impaired object recognition,which is prevented by administration of atypical antipsychotic drug clozapinebut not typical antipsychotics haloperidol.3.DISC1 L100 P homozygousmutant shows normal social activities and social preference.4.L100 P mutant shows impaired social recognition memory after exposure to 3-weeks isolation stress during adolescence?5-8w age?.Wild-type littermate shows normal social memory after adolescent isolation stress.5.Fluo-4 AM Ca²⁺ image analysis revealed suppression of glutamate-evoked elevation of cytoplasmic [Ca²⁺] in DG and CA1 of L100 P slices,indicating that DISC1 L100 P mutation reduces activity of hippocampal neuronal network.6.f EPSPs recording in the SC-CA1 synapses of L100 P hippocampal slices revealed normal basal synaptic transmission,but impaired short-term and long time synaptic plasticity,including abnormal PPF,PTP and LTP.7.L100 P mutant slices exhibit decreased excitatory synaptic transmission?s EPSCs and m EPSCs?while intact inhibitory synaptic transmission?s IPSCs and m IPSCs?in dentate gyrus?DG?.8.Primary cultured L100 P hippocampal neurons?DIV 21days?exhibits normal expression of excitatory synaptic markers,normal excitatory synapse intensity and normal dendrites morphology.9.L100 P mutant mice showed decreased adult neurogenesis in DG.In conclusion,our findings suggest that the existence of abnormal synaptic transmission and plasticity in hippocampal network may disrupt declarative information processing and contribute to recognition deficits in DISC1 L100 P mutant mice.