Dr. Buonanno's laboratory has a general interest in investigating molecular pathways that regulate neuronal plasticity, and that may contribute to understanding complex processes such as behavior and neurological disease. Studies in his laboratory have focused on the Neuregulin (NRG) family of trophic and differentiation factors, which have been shown to modulate neuronal development, synaptic plasticity and behavior. Recent genetic linkage studies with Finish and Irish families have implicated NRGs, and their receptors (ErbB 1-4), with the neurological disorder schizophrenia. Results obtained using knock-out mice for either NRG or the ErbB-4 receptor are consistent with the idea that this signaling pathway, which modulates glutamatergic neurotransmission via NMDA receptors, contributes to behaviors associated with this neurological disorder. Previous work from this laboratory demonstrated that co-activation of NMDA and ErbB receptors modifies glutamate receptor subunit expression during neuronal development (Nature 390: 691-694 [1997]). Later work demonstrated that the c-termini of ErbB-4 receptors, like those of NMDA receptors, interact with PSD-95 in a yeast two-hybrid screen. Immunoprecipitation and Immunofluorescence studies showed that NMDA and ErbB receptors form a ternary complex at excitatory glutamatergic synapses (PNAS 97:3596-3601[2000]). These findings are important because PSD-95 is a protein characterized by multiple PDZ-type protein-protein interaction domains that physically couples the entry of calcium through NMDA receptors, to the activation of signaling proteins on the postsynaptic side that modify synaptic plasticity. Moreover, tyrosine phosphorylation modifies the electrophysiological properties and trafficking of NMDA receptors at synapses, an important issue considering that NMDA receptor activity has been implicated by numerous studies to synaptic plasticity (induction of LTP) and to schizophrenia. We are utilizing knock-out mice for different members of the NRG/ErbB signaling pathway, as well as molecular, biochemical and electrophysiological studies, to understand the precise role of this pathway in synaptic plasticity and neurological disease.

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