The Role Of Schizophrenia Gene TMEM108 And ErbB4 In Synaptic Development And Transimission

Schizophrenia(SZ)is a severe and disabling mental illness with dysfunctions in perception,cognition and motivation,characterized by hallucination,delusions,thought disorders,apathy and cognitive deficits.Signal transmission and synaptic plasticity disorders,caused by abnormal neural development,were thought to attribute to Schizoprenia.Neuregulin 1(NRG1)and its receptor epidermal growth factor 4(ErbB4)have been identified as susceptible genes for schizophrenia.A series of studies showed that NRG1/ErbB4 signaling plays a role in signal transmission and higher brain function through regulating key biological processes in cortex development.Such processes include neuron migration,differentiation,synapse formation and so on.However,how NRG/ErbB4 controls cortical neural circuits and its underlying mechanism are great unknown.ErbB4 is restrictedly expressed in interneurons.It is generally believed that mature diffusible NRG1(s NRG1),cleaved from full length NRG1,could bind to ErbB4,activate ErbB4 kinase activity,and promote the downstream signal pathway.Here we studied ErbB4 function in synaptogenesis in the neural development,and tried to answer these questions: Does ErbB4 participate in the synapse formation of different types? Whether it acts in a kinase activity dependent or independent way?In the first part,we used the ErbB4 null mice,ErbB4-report mice and T796G-ErbB4(an ErbB4 analog sensitive mutant)mice,and studied the role ErbB4 plays in the formation and maturation of different kinds of cortical synapses,by recruiting appropriate methods such as cell culturing,Immunohistochemistry,Western blot,and other molecular methods.We found,1)lack of ErbB4 could neither affect the excitatory synaptogenesis in pyramidal neurons nor influence the inhibitory synaptogenesis in interneurons;2)lacking ErbB4,significantly blocked both excitatory synaptogenesis in interneurons and inhibitory synaptogenesis in pyramidal neurons;3)Chemical inhibitor AG1487 and PD158780,widely inhibit all kinds of synapse formation in both neurons;4)specifically inhibiting ErbB4 kinase activity by 1NMPP1,significantly reduced the excitatory synapse formation and maturation in interneurons,and did not alter the inhibitory synaptogenesis of both neurons,which showed ErbB4 kinase activity is dispensable for inhibitory synapse formation.Our results show that ErbB4 regulate synaptogenesis of pyramidal neurons and interneurons,although the underlying mechanisms may be different.These results implicated ErbB4 in the interneurons could directly or indirectly control pyramidal neurons activity,and then might play a role in neural signal transduction and integration.Moreover,our study suggests a possible pathogenetic mechanism of schizophrenia on the synapse level,which may provide new insights into the clinical medication of schizophrenia.Genetic,psychological and environmental factors contribute to schizophrenia,but the pathogenesis underlying the disorder is still unclear.A leading hypothesis is that schizophrenia is associated with a number of small genetic mutations combine together.TMEM108,which encodes transmembrane protein 108,is one of those genes.However,TMEM108 protein was little known.Here in the second part,we used TMEM108 knockout and Lac Z knockin mice(here we called TMEM108-/-mice),and studied the expression and function of TMEM108 in the brain.We found: 1)TMEM108 expression is developmentally regulated and highly enriched in the dentate gyrus(DG)molecular layer;2)synaptic structure was altered as TMEM108-/-mice had increased filopodia synapses with a concomitant decrease in mushroom body synapses;3)TMEM108-/-mice showed reduced excitatory synaptic transmission and miniature excitatory postsynaptic currents(m EPSC)amplitude without changing the inhibitory transmission,and these deficits in excitatory transmission appear to be a result of reduced AMPA receptor mediated currents but not NMDA receptor mediated currents;4)TMEM108 might interact with AMPA Glu A2 and regulate its trafficking and surface expression.These data suggest that loss of TMEM108 in vivo impairs excitatory synapse maturation and function,which might show a new sight into schizophrenia pathophysiology.