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GABAergic dysfunction underlies many neurodevelopmental and psychiatric disorders. GABAergic synapses exhibit several forms of plasticity at both pre- and postsynaptic levels. NMDA receptor (NMDAR)-dependent inhibitory long-term potentiation (iLTP) at GABAergic postsynapses requires an increase in surface GABA A Rs through promoted exocytosis; however, the regulatory mechanisms and the neuropathological significance remain unclear. Here we report that the autism-related protein PX-RICS is involved in GABA A R transport driven during NMDAR-dependent GABAergic iLTP. Chemically induced iLTP elicited a rapid increase in surface GABA A Rs in wild-type mouse hippocampal neurons, but not in PX-RICS/RICS-deficient neurons. This increase in surface GABA A Rs required the PX-RICS/GABARAP/14-3-3 complex, as revealed by gene knockdown and rescue studies. iLTP induced CaMKII-dependent phosphorylation of PX-RICS to promote PX-RICS-14-3-3 assembly. Notably, PX-RICS/RICS-deficient mice showed impaired amygdala-dependent fear learning, which was ameliorated by potentiating GABAergic activity with clonazepam. Our results suggest that PX-RICS-mediated GABA A R trafficking is a key target for GABAergic plasticity and its dysfunction leads to atypical emotional processing underlying autism., (Copyright © 2018 The Authors. Published by Elsevier B.V. All rights reserved.)

In the mammalian central nervous system, neurogenesis precedes gliogenesis; neurons are primarily generated at the neural stage, whereas most glial cells are generated perinatally and postnatally. However, the signals that regulate this sequence of events remain unclear. Here we show that Wnt signaling induces neuronal and astroglial differentiation but suppresses oligodendroglial differentiation. We observed that precursor cells infected with a retrovirus encoding beta-catenin differentiated into neurons, while astrocytes developed from uninfected precursor cells surrounding infected cells. As neurogenesis proceeded, expression of the bone morphogenetic proteins (BMPs), BMP2, 4 and 7, progressively increased in the cells infected with the retrovirus encoding beta-catenin. Furthermore, treatment of cells with Noggin, a BMP antagonist, completely inhibited astroglial differentiation but partially restored oligodendroglial differentiation. These results suggest that Wnt signaling indirectly regulates gliogenesis by inducing BMPs in neuronal cells. Thus, cooperation between Wnt and BMP signaling may play a key role in determining the sequence of neurogenesis and gliogenesis.

We examined the subcellular distribution of tumor suppressor adenomatous polyposis coli (APC) in developing cultured rat hippocampal neurons using both immunofluorescent microscopy and immunoelectron microscopy. APC initially localized at the distal tips of all the cell processes. Between 12 and 24 h after plating, APC concentrated at the growth cone and in the distal portion of the longest process, which was growing very rapidly. The other processes, growing at a much slower rate, showed only weak immunoreactivity for APC. After maturation of the neurons, APC in the axons was restricted to the growth cones and distal portions. In contrast, APC formed a punctuated pattern along the dendritic processes. This subcellular distribution of APC was dependent on the organization of microtubules, but not actin filaments. Moreover, treatment of neurons with a PKCzeta specific inhibitor caused defects in the staining pattern of APC. These results suggest that APC may be involved in neuronal process extension, and that APC may exert different functions on axons and dendritic processes.

Neural precursor cells (NPCs) have the ability to self-renew and to give rise to neuronal and glial lineages. The fate decision of NPCs between proliferation and differentiation determines the number of differentiated cells and the size of each region of the brain. However, the signals that regulate the timing of neuronal differentiation remain unclear. Here, we show that Wnt signaling inhibits the self-renewal capacity of mouse cortical NPCs, and instructively promotes their neuronal differentiation. Overexpression of Wnt7a or of a stabilized form of beta-catenin in mouse cortical NPC cultures induced neuronal differentiation even in the presence of Fgf2, a self-renewal-promoting factor in this system. Moreover, blockade of Wnt signaling led to inhibition of neuronal differentiation of cortical NPCs in vitro and in the developing mouse neocortex. Furthermore, the beta-catenin/TCF complex appears to directly regulate the promoter of neurogenin 1, a gene implicated in cortical neuronal differentiation. Importantly, stabilized beta-catenin did not induce neuronal differentiation of cortical NPCs at earlier developmental stages, consistent with previous reports indicating self-renewal-promoting functions of Wnts in early NPCs. These findings may reveal broader and stage-specific physiological roles of Wnt signaling during neural development.

Inhibitor of beta-catenin and T cell factor (ICAT) inhibits Wnt signaling by interfering with the interaction between beta-catenin and T cell factor. Here we show that ICAT(-/-) embryos exhibit malformation of the forebrain and craniofacial bones and lack the kidney. Analysis of the neuronal differentiation of embryonic stem cells revealed that Wnt3a redirects the fate of neural progenitors to a posterior character, whereas ICAT induces forebrain cells by inhibiting Wnt signaling. Furthermore, ICAT(-/-) embryonic stem cells were found to differentiate into neuronal cells possessing a posterior character. These results suggest that ICAT plays an important role in the anteriorization of neural cells by inhibiting the posteriorizing activity of Wnt signaling.

Mutations in the adenomatous polyposis coli (APC) gene are associated with familial adenomatous polyposis and sporadic colorectal tumours. The APC gene is expressed ubiquitously in various tissues, especially throughout the large intestine and central nervous system (CNS). In the CNS, the expression of the APC protein is highest during embryonic and early postnatal development. APC associates through its C-terminal region with postsynaptic density (PSD)-95, a neuronal protein that participates in synapse development. Here, we examined the involvement of APC in synaptogenesis. In cultured hippocampal neurons, both overexpression of a dominant-negative construct that disrupts the APC–PSD-95 interaction and knockdown of APC expression using small interfering RNA (siRNA) inhibited the clustering of PSD-95 and a glutamate receptor subunit, and reduced alpha-amino-3-hydroxy-5-methyl-isoxazole-4-propionate (AMPA)-induced activity of AMPA receptors; however, the clustering of an N-methyl-d-aspartate (NMDA) receptor subunit was unaffected. These results are suggestive of APC involvement in the development of glutamatergic synapses. [ABSTRACT FROM AUTHOR]

The Rho family of small GTPases, including RhoA, Rac1 and Cdc42, are critical regulators of the actin cytoskeleton. In neuronal systems, Rho GTPase-activating proteins (RhoGAPs) and their substrates, Rho GTPases, have been implicated in regulating multiple processes in the morphological development of neurons, including axonal growth and guidance, dendritic elaboration and formation of synapses. RICS is mainly expressed in the brain and functions as a RhoGAP protein for Cdc42 and Rac1 in vitro. To examine the biological function of RICS, we disrupted the RICS gene in mice. RICS knockout mice developed normally and were fertile. However, when cultured in vitro, Cdc42 activity in RICS –/– neurons was higher than that in wild-type neurons. Consistent with this finding, hippocampal and cerebellar granule neurons derived from RICS –/– mice bore longer neurites than those from wild-type mice. These findings suggest that RICS plays an important role in neurite extension by regulating Cdc42 in vivo. [ABSTRACT FROM AUTHOR]