Although this finding suggests a minor role for ErbB4 in directly modulating transmitter release in CA1, evidence for ErbB4 in baskets in the prefrontal cortex (Woo et al., 2007) and in Z-FA-FMK a subset of CCK basket terminals in the subiculum (this study) indicate that ErbB4 could modulate presynaptic function in a region- and interneuron subtype-selective manner. Although at first glance reduced excitatory transmission onto GABAergic interneurons would be expected to cause a reduction in inhibitory drive, experiments in the mouse prefrontal cortex (Woo et al., 2007) and the hippocampus (Buonanno and Bui, unpublished observations) show that NRG-1 actually causes an increase in the magnitude of evoked IPSCs on pyramidal neurons. transcriptionCPCR. Contrary to some previous reports, we also Rabbit polyclonal to AMACR did not detect processed ErbB4 fragments or nuclear ErbB4 immunoreactivity. Ultrastructural analysis in CA1 interneurons using immunoelectron microscopy revealed abundant ErbB4 expression in the somatodendritic compartment in which it accumulates at, and adjacent to, glutamatergic postsynaptic sites. In contrast, we found no evidence for presynaptic expression in cultured GAD67-positive hippocampal interneurons and in CA1 basket cell terminals. Our findings identify ErbB4-expressing interneurons, but not pyramidal neurons, as a main target of NRG signaling in the hippocampus and, furthermore, implicate ErbB4 as a selective marker for glutamatergic synapses on inhibitory interneurons. Introduction The receptor tyrosine kinase ErbB4 binds users of the Neuregulin (NRG) and epidermal growth factor (EGF) [betacellulin, HB-EGF (heparin-binding EGF), epiregulin] families of trophic and differentiation factors to regulate a diverse array of neuronal processes, including migration, differentiation, neurotransmission, and synaptic plasticity (for review, see Buonanno and Fischbach, 2001; Mei and Xiong, 2008). ErbB4 is usually expressed in the developing and adult cerebral cortex, and represents the major NRG receptor in central neurons (Lai and Lemke, 1991; Steiner et al., 1999; Gerecke et al., 2001; Yau et al., 2003; Fox and Kornblum, 2005). At Schaffer collateral-to-CA1 (SCCCA1) glutamatergic synapses in the adult hippocampus, NRG-1/ErbB signaling inhibits and reverses (depotentiates) long-term potentiation (LTP) (Huang et al., 2000; Kwon et al., 2005; Bjarnadottir et al., 2007). ErbB receptor activation acutely triggers dopamine release in the hippocampus, and LTP depotentiation by NRG-1 depends on the activation of D4 dopamine receptors to reduce synaptic levels of AMPA-type ionotropic glutamate receptors (Kwon et al., 2008). Conversely, LTP is usually enhanced in ErbB4-deficient mice (Pitcher et al., 2008). These studies suggest that NRG-1/ErbB4 signaling is usually involved in the homeostatic control of glutamatergic plasticity in the adult hippocampus, at least in part via recruitment of a dopaminergic signaling pathway. In addition to its effects on glutamatergic plasticity of CA1 pyramidal neurons, other studies suggest an important role of ErbB signaling for GABAergic function in the adult cortex. In CA3, NRG-1/ErbB4 signaling potently increases the power of kainate-induced gamma oscillations, suggesting that ErbB4 is usually involved in the synchronization of CA3 pyramidal cell firing by local parvalbumin (PV)-expressing basket cell interneurons, Z-FA-FMK many of which express ErbB4 (Fisahn et al., 2009). Consistent with this obtaining, both the quantity of PV-interneurons and the power of kainate-induced gamma oscillations are reduced in ErbB4-knock-out (KO) mice (Fisahn et al., 2009). In the mouse prefrontal cortex, NRG-1 signaling via ErbB4 was shown to modulate GABAergic transmission by augmenting depolarization-induced transmitter release (Woo et al., 2007). The primary cellular and subcellular locus of ErbB4 signaling that underlies the regulation of plasticity at SCCCA1 synapses has not been identified. hybridization studies in the adult rodent and monkey cortex have consistently demonstrated scattered ErbB4 mRNA distribution indicative of expression in interneurons (Lai and Lemke, 1991; Steiner et al., 1999; Huang et al., 2000; Gerecke et al., 2001; Fox and Kornblum, 2005; Thompson et al., 2007). Consistent with these findings, most immunofluorescence analyses recognized strong ErbB4 immunoreactivity (IR) in GABAergic interneurons in dissociated hippocampal neuron cultures and in the cerebral cortex (Garcia et al., 2000; Huang et al., 2000; Gerecke et al., 2001; Yau et al., 2003; Longart et al., 2007). In contrast, the presence of ErbB4 in pyramidal neurons has been a matter of argument. Several histological studies reported ErbB4-IR in pyramidal neurons in the rodent and monkey cortex (Gerecke et al., 2001; Ma et al., 2003; Mechawar et al., 2007; Thompson et al., 2007), but these findings are at variance with the distribution of ErbB4 Z-FA-FMK mRNA, as noted by some (Gerecke et al., 2001; Thompson et al., 2007). Because of the rapidly growing quantity of studies linking NRG-1/ErbB signaling to the modulation of pyramidal neuron properties, such as dendritic spine morphology (Li et al., 2007; Chen et al., 2008; Barros et al., 2009), glutamate receptor trafficking (Gu et al., 2005), and.