BMP7 released by bone marrow stromal cells induces reversible senescence of prostate cancer stem-like cells, and BMPR2 expression inversely correlates with bone metastasis and recurrence in prostate cancer patients.

Neuregulin 1 (NRG1) is a trophic factor thought to play a role in neural development. Recent studies suggest that it may regulate neurotransmission, mechanisms of which remain elusive. Here we show that NRG1, via stimulating GABA release from interneurons, inhibits pyramidal neurons in the prefrontal cortex (PFC). Ablation of the NRG1 receptor ErbB4 in parvalbumin (PV)-positive interneurons prevented NRG1 from stimulating GABA release and from inhibiting pyramidal neurons. PV-ErbB4 −/− mice exhibited schizophrenia-relevant phenotypes similar to those observed in NRG1 or ErbB4 null mutant mice, including hyperactivity, impaired working memory, and deficit in prepulse inhibition (PPI) that was ameliorated by diazepam, a GABA enhancer. These results indicate that NRG1 regulates the activity of pyramidal neurons by promoting GABA release from PV-positive interneurons, identifying a critical function of NRG1 in balancing brain activity. Because both NRG1 and ErbB4 are susceptibility genes of schizophrenia, our study provides insight into potential pathogenic mechanisms of schizophrenia and suggests that PV-ErbB4 −/− mice may serve as a model in the study of this and relevant brain disorders.is a family of trophic factors with an epidermal growth factor (EGF)-like domain (1, 2). It acts by stimulating the ErbB family of receptor tyrosine kinases ErbB2, -3, and -4. NRG1 binds only to ErbB3 or ErbB4, but not to ErbB2. On the other hand, ErbB2 and ErbB4 are most active in response to NRG1 stimulation whereas the kinase activity of ErbB3 is impaired. Thus, ErbB2 and ErbB3 function by forming heterodimers with each other or with ErbB4, but an ErbB4 homodimer is functional by itself (2). NRG1 has been implicated in many aspects of neural development including neuron migration, axon projection, myelination, synapse formation, and up-regulation of neurotransmitter receptor expression (2). Recently, CNS-specific mutation of ErbB2 and ErbB4 seemed to have no effect on layered structures of the cerebral cortex, hippocampus, and cerebellum or expression of NMDA receptor subtypes (3, 4), challenging existing views of NRG1 function.Both NRG1 and its receptors are distributed throughout brain regions critical for higher function in adult animals (5-8), suggesting a role of NRG1 in the brain after neural development is complete. In support of this hypothesis were observations that ErbB4 is present at the postsynaptic density of excitatory synapses presumably via interaction with PSD-95 (9-11). Moreover, ErbB4 mRNA is enriched in regions where interneurons are clustered (5) and GAD-positive neurons of the hippocampus express high levels of ErbB4 (10), suggesting that ErbB4 is enriched in GABAergic neurons. Immunohistochemical analysis indicates that ErbB4 is expressed in most if not all parvalbumin (PV)-positive interneurons in addition to glutamatergic neurons (10, 12). Intriguingly, exogenous NRG1 suppresses the induction of LTP at Schaffer collateral-CA1 synapses in the hippocampus (10, 11, 13) or reverses it (14, 15). These observ...

Neuregulin 1 (NRG1) is a trophic factor that acts by stimulating ErbB receptor tyrosine kinases and has been implicated in neural development and synaptic plasticity. In this study, we investigated mechanisms of its suppression of long-term potentiation (LTP) in the hippocampus. We found that NRG1 did not alter glutamatergic transmission at SC-CA1 synapses but increased the GABA A receptormediated synaptic currents in CA1 pyramidal cells via a presynaptic mechanism. Inhibition of GABA A receptors blocked the suppressing effect of NRG1 on LTP and prevented ecto-ErbB4 from enhancing LTP, implicating a role of GABAergic transmission. To test this hypothesis further, we generated parvalbumin (PV)-Cre;ErbB4 −/− mice in which ErbB4, an NRG1 receptor in the brain, is ablated specifically in PV-positive interneurons. NRG1 was no longer able to increase inhibitory postsynaptic currents and to suppress LTP in PV-Cre; ErbB4 −/− hippocampus. Accordingly, contextual fear conditioning, a hippocampus-dependent test, was impaired in PV-Cre;ErbB4 −/− mice. In contrast, ablation of ErbB4 in pyramidal neurons had no effect on NRG1 regulation of hippocampal LTP or contextual fear conditioning. These results demonstrate a critical role of ErbB4 in PV-positive interneurons but not in pyramidal neurons in synaptic plasticity and support a working model that NRG1 suppresses LTP by enhancing GABA release. Considering that NRG1 and ErbB4 are susceptibility genes of schizophrenia, these observations contribute to a better understanding of how abnormal NRG1/ErbB4 signaling may be involved in the pathogenesis of schizophrenia. N euregulin 1 (NRG1) is a trophic factor that acts by activating ErbB receptor tyrosine kinases, including ErbB4. NRG1 signaling has been implicated in various steps in neural development, including neuron migration, axon guidance, synapse formation, and expression of neurotransmitter receptors (1). Studies of NRG1 have attracted much attention because both NRG1 and ErbB4 were identified as susceptibility genes of schizophrenia and NRG1 and ErbB4 mutant mice show schizophrenia-relevant behaviors (1-4).Recent studies suggest that NRG1 plays a role in neurotransmission and synaptic plasticity (1). NRG1 has been shown to suppress the induction of LTP acutely at Schaffer collateral (SC)-CA1 synapses in adult rodent hippocampus (5-8), but it has no effect on basal synaptic transmission (5, 7, 9). NRG1 regulation of long-term potentiation (LTP) requires ErbB4 (8); however, underlying mechanisms remain unclear. In vitro studies suggest that NRG1 may alter functions of pyramidal neurons and glutamatergic transmission. For example, it could suppress NMDA receptor (NMDAR) currents in prefrontal cortical (PFC) neurons in culture (10). NRG1 was shown to stimulate internalization of surface AMPA receptors (AMPARs) in dissociated hippocampal neurons (11). Moreover, changes in ErbB4 levels in neonatal hippocampal slices alter dendritic spine size and AMPA synaptic currents (12). Conversely, ErbB4 expression is largely restricted to ...

The retromer complex component VPS35 prevents activation of the BACE1 and Aβ production and thus plays an essential role in limiting Alzheimer’s disease neuropathology.

Triggering receptor expressed on myeloid cells 2 (TREM2) is a microglial surface receptor genetically linked to the risk for Alzheimer’s disease (AD). A proteolytic product, soluble TREM2 (sTREM2), is abundant in the cerebrospinal fluid and its levels positively correlate with neuronal injury markers. To gain insights into the pathological roles of sTREM2, we studied sTREM2 in the brain of 5xFAD mice, a model of AD, by direct stereotaxic injection of recombinant sTREM2 protein or by adeno-associated virus (AAV)-mediated expression. We found that sTREM2 reduces amyloid plaque load and rescues functional deficits of spatial memory and long-term potentiation. Importantly, sTREM2 enhances microglial proliferation, migration, clustering in the vicinity of amyloid plaques and the uptake and degradation of Aβ. Depletion of microglia abolishes the neuroprotective effects of sTREM2. Our study demonstrates a protective role of sTREM2 against amyloid pathology and related toxicity and suggests that increasing sTREM2 can be explored for AD therapy.

Neuregulin 1 (NRG1) and its receptor ErbB4 are both susceptibility genes of schizophrenia. However, little is known about the underlying mechanisms of their malfunction. Although ErbB4 is enriched in GABAergic interneurons, the role of NRG1 in excitatory synapse formation in these neurons remains poorly understood. We showed that NRG1 increased both the number and size of PSD-95 puncta and the frequency and amplitude of miniature EPSCs (mEPSCs) in GABAergic interneurons, indicating that NRG1 stimulates the formation of new synapses and strengthens existing synapses. In contrast, NRG1 treatment had no effect on either the number or size of excitatory synapses in glutamatergic neurons, suggesting its synaptogenic effect is specific to GABAergic interneurons. Ecto-ErbB4 treatment diminished both the number and size of excitatory synapses, suggesting that endogenous NRG1 may be critical for basal synapse formation. NRG1 could stimulate the stability of PSD-95 in the manner that requires tyrosine kinase activity of ErbB4. Finally, deletion of ErbB4 in parvalbumin-positive interneurons led to reduced frequency and amplitude of mEPSCs, providing in vivo evidence that ErbB4 is important in excitatory synaptogenesis in interneurons. Together, our findings suggested a novel synaptogenic role of NRG1 in excitatory synapse development, possibly via stabilizing PSD-95, and this effect is specific to GABAergic interneurons. In light of the association of the genes of both NRG1 and ErbB4 with schizophrenia and dysfunction of GABAergic system in this disorder, these results provide insight into its potential pathological mechanism.

LGI1 in humans is responsible for a predisposition to autosomal dominant partial epilepsy with auditory features (ADPEAF). However, mechanisms of how LGI1 mutations cause epilepsy remain unclear. We have used a mouse chromosome engineering strategy to create a null mutation for the gene ortholog encoding LGI1. The Lgi1 null mutant mice show no gross overall developmental abnormalities from routine histopathological analysis. After 12-18 days of age, the homozygous mutant mice all exhibit myoclonic seizures accompanied by rapid jumping and running and die shortly thereafter. The heterozygous mutant mice do not develop seizures. Electrophysiological analysis demonstrates an enhanced excitatory synaptic transmission by increasing the release of the excitatory neurotransmitter glutamate, suggesting a basis for the seizure phenotype. This mouse model, therefore, provides novel insights into the mechanism behind ADPEAF and offers a new opportunity to study the mechanism behind the role of LGI1 in susceptibility to myoclonic seizures.

BackgroundVacuolar protein sorting 35 (VPS35), a key component of retromer, plays an important role in endosome-to-Golgi retrieval of membrane proteins. Dysfunction of VPS35/retromer is a risk factor for neurodegenerative disorders, including AD (Alzheimer’s disease) and PD (Parkinson’s disease). However, exactly how VPS35-deficiency contributes to AD or PD pathogenesis remains poorly understood.ResultsWe found that VPS35-deficiency impaired dendritic spine maturation and decreased glutamatergic transmission. AMPA receptors, GluA1 and GluA2, are significantly reduced in purified synaptosomal and PSD fractions from VPS35-deficient brain. The surface levels of AMPA receptors are also decreased in VPS35-deficient neurons. Additionally, VPS35 interacted with AMPA-type receptors, GluA1 and GluA2. Overexpression of GluA2, but not GluA1, could partially restore the spine maturation deficit in VPS35-deficient neurons.ConclusionsThese results provide evidence for VPS35’s function in promoting spine maturation, which is likely through increasing AMPA receptor targeting to the postsynaptic membrane. Perturbation of such a VPS35/retromer function may contribute to the impaired glutamatergic transmission and pathogenesis of neurodegenerative disorders, such as AD and PD.Electronic supplementary materialThe online version of this article (doi:10.1186/s13041-015-0156-4) contains supplementary material, which is available to authorized users.