Islet-brain-2: A novel postsynaptic density protein linked to an autism spectrum disorder

Islet-brain-2 (IB2) is a neuronal protein, whose functions are not well understood. Based upon its sequence homology to JNK-interacting protein 1 (JIP1) and biochemical studies, IB2 has been described as a putative scaffold for mitogen activated protein kinase (MAPK) signaling. IB2 has been documented to interact with a wide array of functionally unrelated proteins, which has complicated efforts to confirm its biochemical role in vivo. In order to investigate the IB2 function in the nervous system, we have generated Ib2 null mice. The mutants are viable and their expression of genes neighboring Ib2 is unaffected. Ib2 knockout mice display developmental delay in grip strength until 5 weeks (P35) of age. Their behavioral analysis following disappearance of this defect shows significant deficits in their motor learning abilities. In addition, mutant mice exhibit marked reduction in social interactions, delayed fear induced learning and unresponsiveness to the environment in various behavioral tasks. These complex atypical behaviors are reminiscent of autism spectrum disorders (ASDs). Interestingly, the human Ib2 gene resides within the deleted chr22qter region in Phelan-McDermid syndrome and patients with this disorder manifest similar deficits as observed in our Ib2 null mice, suggesting that Ib2 loss-of-function is a promising candidate model for this disorder. Recent developments in the ASDs field implicate as a major culprit defective synaptic function. Using brain fractionation and co-immunoprecipitation methods, we show that IB2 is an integral component of the postsynaptic density (PSD). Immunofluorescence shows IB2 concentrated within dendritic spine heads. Ib2 mutation did not alter expression levels of many other common PSD components such as PSD95 and AMPA-type and NMDA-type receptors subunits. Signaling analyses conducted in Ib2 null cultured cortical neurons failed to reveal deficits in NMDA-evoked signaling through known IB2-interacting partners TIAM1 and p38MAPK, suggesting that IB2 modulates synaptic and behavioral functions through as yet unknown molecular mechanisms.