Silent synapses generate sparse and orthogonal action potential firing in adult-born hippocampal granule cells.

In adult neurogenesis young neurons connect to the existing network via formation of thousands of new synapses. At early developmental stages, glutamatergic synapses are sparse, immature and functionally 'silent', expressing mainly NMDA receptors. Here we show in 2- to 3-week-old young neurons of adult mice, that brief-burst activity in glutamatergic fibers is sufficient to induce postsynaptic AP firing in the absence of AMPA receptors. The enhanced excitability of the young neurons lead to efficient temporal summation of small NMDA currents, dynamic unblocking of silent synapses and NMDA-receptor-dependent AP firing. Therefore, early synaptic inputs are powerfully converted into reliable spiking output. Furthermore, due to high synaptic gain, small dendritic trees and sparse connectivity, neighboring young neurons are activated by different distinct subsets of afferent fibers with minimal overlap. Taken together, synaptic recruitment of young neurons generates sparse and orthogonal AP firing, which may support sparse coding during hippocampal information processing

Discovery and Characterization of an Endogenous CXCR4 Antagonist

CXCL12-CXCR4 signaling controls multiple physiological processes and its dysregulation is associated with cancers and inflammatory diseases. To discover as-yet-unknown endogenous ligands of CXCR4, we screened a blood-derived peptide library for inhibitors of CXCR4-tropic HIV-1 strains. This approach identified a 16 amino acid fragment of serum albumin as an effective and highly specific CXCR4 antagonist. The endogenous peptide, termed EPI-X4, is evolutionarily conserved and generated from the highly abundant albumin precursor by pH-regulated proteases. EPI-X4 forms an unusual lasso-like structure and antagonizes CXCL12-induced tumor cell migration, mobilizes stem cells, and suppresses inflammatory responses in mice. Furthermore, the peptide is abundant in the urine of patients with inflammatory kidney diseases and may serve as a biomarker. Our results identify EPIX4 as a key regulator of CXCR4 signaling and introduce proteolysis of an abundant precursor protein as an alternative concept for chemokine receptor regulation

Bidirectional GABAergic control of action potential firing in newborn hippocampal granule cells.

Newly generated young neurons in the adult hippocampus receive GABAergic synaptic inputs, which are crucial for activity-dependent survival and functional maturation between 1-3 weeks after mitosis. We found synaptically driven action potential (AP) firing in these newborn young cells in adult mice. Although glutamatergic synaptic inputs remained subthreshold, activation of GABAergic synaptic inputs depolarized young neurons and reliably evoked APs. Furthermore, pairing of subthreshold excitatory postsynaptic potentials or somatic current injection with brief bursts of GABAergic inputs revealed efficient GABAergic excitation at conductances of ∼ 1.5 nS, corresponding to the activity of only three or four interneurons. Stronger GABAergic inputs (>4 nS) effectively blocked AP firing via shunting inhibition, which might be important to dynamically control spiking output in both directions. Taken together, GABAergic interneurons differentially recruit newborn young granule cells by supporting either AP generation or shunting inhibition dependent on hippocampal network activity

Reacquisition of Nef-Mediated Tetherin Antagonism in a Single In Vivo Passage of HIV-1 through Its Original Chimpanzee Host

The interferon-induced host restriction factor tetherin poses a barrier for SIV transmission from primates to humans. Following cross-species transmission, the chimpanzee precursor of pandemic HIV-1 switched from the accessory protein Nef to Vpu to effectively counteract human tetherin. As we report here, the experimental reintroduction of HIV-1 into its original chimpanzee host resulted in a virus that can use both Vpu and Nef to antagonize chimpanzee tetherin. Functional analyses demonstrated that alterations in and near the highly conserved ExxxLL motif in the C-terminal loop of Nef were critical for the reacquisition of anti-tetherin activity. Strikingly, just two amino acid changes allowed HIV-1 Nef to counteract chimpanzee tetherin and promote virus release. Our data demonstrate that primate lentiviruses can reacquire lost accessory gene functions during a single in vivo passage and suggest that other functional constraints keep Nef ready to regain anti-tetherin activity

Nef proteins of epidemic HIV-1 group O strains antagonize human tetherin

Most simian immunodeficiency viruses use their Nef protein to antagonize the host restriction factor tetherin. A deletion in human tetherin confers Nef resistance, representing a hurdle to successful zoonotic transmission. HIV-1 group M evolved to utilize the viral protein U (Vpu) to counteract tetherin. Although HIV-1 group O has spread epidemically in humans, it has not evolved a Vpu-based tetherin antagonism. Here we show that HIV-1 group O Nef targets a region adjacent to this deletion to inhibit transport of human tetherin to the cell surface, enhances virion release, and increases viral resistance to inhibition by interferon-alpha. The Nef protein of the inferred common ancestor of group O viruses is also active against human tetherin. Thus, Nef-mediated antagonism of human tetherin evolved prior to the spread of HIV-1 group O and likely facilitated secondary virus transmission. Our results may explain the epidemic spread of HIV-1 group O

Human tetherin exerts strong selection pressure on the HIV-1 group N Vpu protein

HIV-1 groups M and N emerged within the last century following two independent cross-species transmissions of SIVcpz from chimpanzees to humans. In contrast to pandemic group M strains, HIV-1 group N viruses are exceedingly rare, with only about a dozen infections identified, all but one in individuals from Cameroon. Poor adaptation to the human host may be responsible for this limited spread of HIV-1 group N in the human population. Here, we analyzed the function of Vpu proteins from seven group N strains from Cameroon, the place where this zoonosis originally emerged. We found that these N-Vpus acquired four amino acid substitutions (E15A, V19A and IV25/26LL) in their transmembrane domain (TMD) that allow efficient interaction with human tetherin. However, despite these adaptive changes, most N-Vpus still antagonize human tetherin only poorly and fail to down-modulate CD4, the natural killer (NK) cell ligand NTB-A as well as the lipid-antigen presenting protein CD1d. These functional deficiencies were mapped to amino acid changes in the cytoplasmic domain that disrupt putative adaptor protein binding sites and an otherwise highly conserved beta TrCP-binding DSGxxS motif. As a consequence, N-Vpus exhibited aberrant intracellular localization and/or failed to recruit the ubiquitin-ligase complex to induce tetherin degradation. The only exception was the Vpu of a group N strain recently discovered in France, but originally acquired in Togo, which contained intact cytoplasmic motifs and counteracted tetherin as effectively as the Vpus of pandemic HIV-1 M strains. These results indicate that HIV-1 group N Vpu is under strong host-specific selection pressure and that the acquisition of effective tetherin antagonism may lead to the emergence of viral variants with increased transmission fitness

Nef proteins of epidemic HIV-1 group O strains antagonize human tetherin

Most simian immunodeficiency viruses use their Nef protein to antagonize the host restriction factor tetherin. A deletion in human tetherin confers Nef resistance, representing a hurdle to successful zoonotic transmission. HIV-1 group M evolved to utilize the viral protein U (Vpu) to counteract tetherin. Although HIV-1 group O has spread epidemically in humans, it has not evolved a Vpu-based tetherin antagonism. Here we show that HIV-1 group O Nef targets a region adjacent to this deletion to inhibit transport of human tetherin to the cell surface, enhances virion release, and increases viral resistance to inhibition by interferon-alpha. The Nef protein of the inferred common ancestor of group O viruses is also active against human tetherin. Thus, Nef-mediated antagonism of human tetherin evolved prior to the spread of HIV-1 group O and likely facilitated secondary virus transmission. Our results may explain the epidemic spread of HIV-1 group O

Discovery and Characterization of an Endogenous CXCR4 Antagonist

CXCL12-CXCR4 signaling controls multiple physiological processes and its dysregulation is associated with cancers and inflammatory diseases. To discover as-yet-unknown endogenous ligands of CXCR4, we screened a blood-derived peptide library for inhibitors of CXCR4-tropic HIV-1 strains. This approach identified a 16 amino acid fragment of serum albumin as an effective and highly specific CXCR4 antagonist. The endogenous peptide, termed EPI-X4, is evolutionarily conserved and generated from the highly abundant albumin precursor by pH-regulated proteases. EPI-X4 forms an unusual lasso-like structure and antagonizes CXCL12-induced tumor cell migration, mobilizes stem cells, and suppresses inflammatory responses in mice. Furthermore, the peptide is abundant in the urine of patients with inflammatory kidney diseases and may serve as a biomarker. Our results identify EPI-X4 as a key regulator of CXCR4 signaling and introduce proteolysis of an abundant precursor protein as an alternative concept for chemokine receptor regulation