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Causes clustering of PSD-95

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Abbreviations: NMDAR, A-methyl-D-aspartate receptor; PSD-95, postsynaptic density protein 95; RNAi, RNA interference.

Abbreviations: NMDAR, A-methyl-D-aspartate receptor; PSD-95, postsynaptic density protein 95; RNAi, RNA interference.

members, and all unrelated controls analyzed. Support for the involvement of neuroligin 4 with autism followed from a large study of autistic individuals, where 4 missense mutations in neuroligin 4 were identified51. In agreement, a two base pair deletion in neuroligin 4, leading to a truncation in the expressed protein (position 429), was identified in a family containing both autistic and nonautistic but mentally retarded family members52. This suggested that neuroligin-associated disorders include both autism and mental retardation, and thus that these two syndromes may involve a common synaptic mechanism. However, controversy has arisen over the association of autism with neuroligin gene mutations. In two other studies involving larger populations, neuroligin mutations were not identified in association with autism53'54. Although these studies do not rule out a role for neuroligin, they suggest that it may only be responsible for a small percentage of the heterogeneous population suffering from autism55 and mental retardation56.

To further the investigation into the role that neuroligin mutations may play in nervous system disorders, constructs of neuroligins 3 and 4 encoding the previously identified disease-associated mutations R451C and D396X50, were generated and transfected into heterologous cells57,59. Only low levels of neuroligin 3 R451C (and the corresponding mutation R471C in rat neuroligin) and no neuroligin 4 D396X were targeted to the cell surface, and co-labeling revealed that both mutant proteins were retained in the endoplasmic reticulum. Upon transfection into hippocampal neurons, the mutants failed to promote presynaptic differentiation57. In a related study using an autism mutant of neuroligin 3 and a comparable mutation site in neuroligin 1, transfections resulted in less efficient trafficking to the cell surface, despite retaining some synaptogenic activity58. Although much work remains to be done to establish its role in disease, the disruption of the neuroligin/neurexin complex may significantly alter the ratio between excitatory and inhibitory neurotransmission, manifesting itself in an impaired cognitive development, and possibly psychiatric disorders such as autism.

7. CONCLUSIONS

Neuroligin and neurexin represent an ideal candidate pair for a role in the formation and/or maturation of synapses due to their heterotypic binding, regulated by alternative splicing and Ca2+ dependence. At least in vitro, neuroligin and ß-neurexin induce pre- and postsynaptic specializations, respectively, including recruitment of relevant synaptic molecules to newly formed synaptic contacts. Through its interaction with PSD-95, the complex seems to be of particular importance for the balance between excitatory and inhibitory synapses. The newly induced synaptic contacts appear functional due to the detection of neurotransmitter release, although this has only been tested by miniature postsynaptic current recordings. Disruption of the ß-neurexin/neuroligin complex in vitro, in turn, results in the abrogation of synaptic structure and function. Based on identified mutations, neuroligins and the neuroligin/ß-neurexin complex are putative candidates for the molecular basis of cognitive diseases such as autism and mental retardation.*

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Aspergers Answers Revealed

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