Regulation of NMDA Receptors by Neuregulin Signaling in Prefrontal Cortex

Abstract

Recent linkage studies have identified a significant association of the neuregulin gene with schizophrenia, but how neuregulin is involved in schizophrenia is primarily unknown. Aberrant NMDA receptor functions have been implicated in the pathophysiology of schizophrenia. Therefore, we hypothesize that neuregulin, which is present in glutamatergic synaptic vesicles, may affect NMDA receptor functions via actions on its ErbB receptors enriched in postsynaptic densities, hence participating in emotional regulation and cognitive processes that are impaired in schizophrenia. To test this, we examined the regulation of NMDA receptor currents by neuregulin signaling pathways in prefrontal cortex (PFC), a prominent area affected in schizophrenia. We found that bath perfusion of neuregulin significantly reduced whole-cell NMDA receptor currents in acutely isolated and cultured PFC pyramidal neurons and decreased NMDA receptor-mediated EPSCs in PFC slices. The effect of neuregulin was mainly blocked by application of the ErbB receptor tyrosine kinase inhibitor, phospholipase C (PLC) inhibitor, IP 3 receptor (IP 3 R) antagonist, or Ca 2ϩ chelators. The neuregulin regulation of NMDA receptor currents was also markedly attenuated in cultured neurons transfected with mutant forms of Ras or a dominant-negative form of MEK1 (mitogen-activated protein kinase kinase 1). Moreover, the neuregulin effect was prevented by agents that stabilize or disrupt actin polymerization but not by agents that interfere with microtubule assembly. Furthermore, neuregulin treatment increased the abundance of internalized NMDA receptors in cultured PFC neurons, which was also sensitive to agents affecting actin cytoskeleton. Together, our study suggests that both PLC/IP 3 R/Ca 2ϩ and Ras/MEK/ERK (extracellular signal-regulated kinase) signaling pathways are involved in the neuregulin-induced reduction of NMDA receptor currents, which is likely through enhancing NR1 internalization via an actin-dependent mechanism.

Neuroprotection by neuregulin-1 in a rat model of permanent focal cerebral ischemia

“…Overexpression of erbB4 enhanced AMPA currents and increased dendritic spine size, while reduced NRG1/erbB4 signaling resulted in glutamatergic hypofunction with a loss of NMDA currents and dendritic spines [23]. Direct effects of NRG-1 on NMDA receptor activity has been demonstrated where bath application of NRG-1 to acutely isolated and cultured pyramidal neurons resulted in a significant reduction of NMDA receptor currents [15].…”

Schizophrenia susceptibility pathway neuregulin 1–ErbB4 suppresses Src upregulation of NMDA receptors

“…To investigate whether NRG1β affects Src-induced enhancement of synaptic NMDARs in another brain region implicated in the pathogenesis of schizophrenia, we studied the prefrontal cortex 43,49,50 . In acute slices from the medial prefrontal cortex, we evoked NMDAR EPSCs in layer V pyramidal neurons by stimulating the corticocortical neurons and afferents in layers II and III while pharmacologically blocking AMPA and GABA receptors.…”

ErbB4 reduces synaptic GABA A currents independent of its receptor tyrosine kinase activity

“…4E, NRG2 results in phosphoactivation of PKCγ but not PKCα/βII. To selectively block PKC activation, we included an inhibitory PKC (19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30)(31)(32)(33)(34)(35)(36) peptide (10 μM) in the intracellular solution. As illustrated in Fig.…”