Extra-synaptic Neuregulin-2 signaling functions in GABAergic and glutamatergic cortical networks

Neuronal excitability and information processing in cortical networks are based on synaptic neurotransmission and modulated by molecular signaling events, which act on synapses as well as extra-synaptic processes, thereby supporting balanced network activity. As changes in excitation/inhibition (E/I) balance represent an organizing framework for the pathophysiology of neuropsychiatric disorders (Sohal and Rubinstein, 2019), a better understanding of molecular signals that modulate neuronal excitability is of great importance for the development of better treatment strategies. An emerging locus of extra-synaptic processes linked to neuronal excitability are endoplasmic reticulum-plasma membrane (ER-PM) junctions; in the case of more stable ER-derived flattened membrane disks, these structures are termed subsurface cisterns (SSC; Rosenbluth, 1962; Takeshima et al., 2015). SSCs may serve as Ca2+ microdomains and as platforms for the structural and functional coupling of proteins, including potassium and calcium channels (Vierra et al., 2021; Johnson et al., 2019). However, the exact protein composition, structural plasticity, and cortical network functions of ER-PM junctions/SSCs in vivo remain not well defined.
Neuregulin 2 (NRG2) belongs to a family of four EGF-like growth factors (NRG1-4) that serve as ligands for receptor tyrosine kinases of the ErbB family (Carraway et al., 1997). ErbB4 serves as the main NRG2 receptor in the brain, and abnormal NRG/ErbB4 signaling has been implicated in several neurological disorders, including schizophrenia (Shi and Bergson, 2020). In contrast to NRG1, NRG2 expression increases with brain development, suggesting important functions in the adult brain (Longart et al., 2004), however NRG2 functions in the adult brain have not been studied in detail. NRG2 is expressed in glutamatergic projection neurons as well as GABAergic interneurons (Yan et al., 2017), where it is co-expressed with ErbB4. The NRG2 pro-protein accumulates as ‘puncta’ atop of SSCs in the plasma membrane of the somato-dendritic compartment of neurons, and NMDA receptor activation in cultured neurons triggers ADAM10 protease-mediated NRG2 ectodomain shedding (including the EGF-like signaling domain), which could initiate autocrine signaling to ErbB4 (Vullhorst et al., 2015; Vullhorst and Buonanno, 2020). A significant fraction of ErbB4 is also extra-synaptic, and treatment of cultured interneurons with the EGF-like domain of NRG2 increases the association of ErbB4 with the GABA1 receptor and results in a decrease of inhibitory currents. Remarkably, the tyrosine kinase activity is dispensable in this context, in line with bidirectional signaling processes (Mitchell et al., 2013). Together, these data indicate that NRG2/ErbB4, GABA1, and NMDA receptors interact to regulate interneuron excitability, but this has not been examined in vivo.

To investigate Neuregulin-2 signaling functions in mature glutamatergic and GABAergic networks in vivo

Biotecnología Médica