Mariana Vargas-Caballero

Tau protein is required for amyloid {beta}-induced impairment of hippocampal long-term potentiation.

Amyloid β (Aβ) and tau protein are both implicated in memory impairment, mild cognitive impairment (MCI), and early Alzheimers disease (AD), but whether and how they interact is unknown. Consequently, we asked whether tau protein is required for the robust phenomenon of Aβ-induced impairment of hippocampal long-term potentiation (LTP), a widely accepted cellular model of memory. We used wild-type mice and mice with a genetic knock-out of tau protein and recorded field potentials in an acute slice preparation. We demonstrate that the absence of tau protein prevents Aβ-induced impairment of LTP. Moreover, we show that Aβ increases tau phosphorylation and that a specific inhibitor of the tau kinase glycogen synthase kinase 3 blocks the increased tau phosphorylation induced by Aβ and prevents Aβ-induced impairment of LTP in wild-type mice. Together, these findings show that tau protein is required for Aβ to impair synaptic plasticity in the hippocampus and suggest that the Aβ-induced impairment of LTP is mediated by tau phosphorylation. We conclude that preventing the interaction between Aβ and tau could be a promising strategy for treating cognitive impairment in MCI and early AD.

Treatment of inflammatory and neuropathic pain by uncoupling Src from the NMDA receptor complex

Chronic pain hypersensitivity depends on N-methyl-D-aspartate receptors (NMDARs). However, clinical use of NMDAR blockers is limited by side effects resulting from suppression of the physiological functions of these receptors. Here we report a means to suppress pain hypersensitivity without blocking NMDARs, but rather by inhibiting the binding of a key enhancer of NMDAR function, the protein tyrosine kinase Src. We show that a peptide consisting of amino acids 40–49 of Src fused to the protein transduction domain of the HIV Tat protein (Src40–49Tat) prevented pain behaviors induced by intraplantar formalin and reversed pain hypersensitivity produced by intraplantar injection of complete Freunds adjuvant or by peripheral nerve injury. Src40–49Tat had no effect on basal sensory thresholds, acute nociceptive responses or cardiovascular, respiratory, locomotor or cognitive functions. Thus, through targeting of Src-mediated enhancement of NMDARs, inflammatory and neuropathic pain are suppressed without the deleterious consequences of directly blocking NMDARs, an approach that may be of broad relevance to managing chronic pain.

Pharmacological targeting of CSF1R inhibits microglial proliferation and prevents the progression of Alzheimer’s-like pathology

Microglial proliferation and activation is a hallmark of Alzheimer’s disease. Olmos-Alonso et al. show that microglial proliferation in Alzheimer’s disease tissue correlates with overactivation of the colony-stimulating factor 1 receptor (CSF1R) pathway. CSF1R blockade arrests microglial proliferation and activation in a mouse model of Alzheimer-like pathology and slows disease progression.

Visual stimuli-induced LTD of GABAergic synapses mediated by presynaptic NMDA receptors

Local GABA (γ-aminobutyric acid) circuits contribute to sensory experience–dependent refinement of neuronal connections in the developing nervous system, but whether GABAergic synapses themselves can be rapidly modified by sensory stimuli is largely unknown. Here we report that repetitive light stimuli or theta burst stimulation (TBS) of the optic nerve in the developing Xenopus retinotectal system induces long-term potentiation (LTP) of glutamatergic inputs but long-term depression (LTD) of GABAergic inputs to the same tectal neuron. The LTD is due to a reduction in presynaptic GABA release and requires activation of presynaptic NMDA (N-methyl-D-aspartate) receptors (NMDARs) and coincident high-level GABAergic activity. Thus, the presynaptic NMDAR may function as a coincidence detector for adjacent glutamatergic and GABAergic activities, leading to coordinated synaptic modification by sensory experience.

In situ measurement of the electrical potential across the phagosomal membrane using FRET and its contribution to the proton-motive force

Phagosomes employ lytic enzymes, cationic peptides, and reactive oxygen intermediates to eliminate invading microorganisms. The effectiveness of these microbicidal mechanisms is potentiated by the acidic pH created by H+-pumping vacuolar-type ATPases (V-ATPases) on the phagosomal membrane. The degree of phagosomal acidification varies greatly among neutrophils, macrophages, and dendritic cells and can be affected by diseases like cystic fibrosis. The determinants of phagosomal pH are not completely understood, but the permeability to ions that neutralize the electrogenic effect of the V-ATPase has been proposed to play a central role. When counterion conductance is limiting, generation of a large membrane potential will dominate the proton-motive force (pmf), with a proportionally diminished pH gradient. Validation of this notion requires direct measurement of the electrical potential that develops across the phagosomal membrane (ΨΦ). We describe a noninvasive procedure to estimate ΨΦ in intact cells, based on fluorescence resonance energy transfer. This approach, in combination with measurements of phagosomal pH, enabled us to calculate the pmf across phagosomes of murine macrophages and to analyze the factors that limit acidification. At steady state, ΨΦ averaged 27 mV (lumen positive) and was only partially dissipated by inhibition of the V-ATPase with concanamycin A. The comparatively small contribution of the potential to the pmf suggests that proton pumping is not limited by the counterion permeability, a notion that was validated independently by using ionophores. Instead, phagosomal pH stabilizes when the rate of proton pumping, which decreases gradually as the lumen acidifies, is matched by the passive leak of proton equivalents.

Fast and slow voltage-dependent dynamics of magnesium block in the NMDA receptor: the asymmetric trapping block model

The NMDA receptor (NMDAR) produces a long-lasting component of the glutamatergic EPSC in mammalian central neurons. The current through NMDARs is voltage dependent as a result of block by extracellular magnesium, which has recently been shown to give rise to a complex time dependence, with fast and slow components of responses to changes in membrane potential. Here, we studied the dynamics of block and unblock by measuring voltage step responses in conjunction with fast perfusion of agonist in nucleated patches isolated from rat cortical pyramidal neurons. We found that slow unblock shows a progressive onset during synaptic-like responses to brief pulses of agonist. Repolarizing briefly from +40 to -70 mV revealed that slow unblock is reestablished with a time constant of ∼5 msec at room temperature. Also, the time course of deactivation, in response to a pulse of agonist, slows twofold over the potential range -30 to +40 mV. An asymmetric “trapping block” model in which the voltage-independent closing rate constant of the blocked channel is approximately three times that of the unblocked channel accounts quantitatively for all of these phenomena and for responses to action potential waveform clamp. This model allows much more accurate prediction of NMDAR current in physiological conditions of magnesium concentration and changing membrane potential than previously possible. It suggests a positive allosteric link between occupation of the NMDAR pore by magnesium and closure of the permeation gate.

Temporal dynamics of hippocampal neurogenesis in chronic neurodegeneration

Increased neurogenesis has been reported in neurodegenerative disease, but its significance is unclear. In a mouse model of prion disease, Gomez-Nicola et al. detect increased neurogenesis in the dentate gyrus that partially counteracts neuronal loss. Targeting neurogenesis may have therapeutic potential.

Synaptic Integration in Electrically Coupled Neurons

Interactions among chemical and electrical synapses regulate the patterns of electrical activity of vertebrate and invertebrate neurons. In this investigation we studied how electrical coupling influences the integration of excitatory postsynaptic potentials (EPSPs). Pairs of Retzius neurons of the leech are coupled by a nonrectifying electrical synapse by which chemically induced synaptic currents flow from one neuron to the other. Results from electrophysiology and modeling suggest that chemical synaptic inputs are located on the coupled neurites, at 7.5 microm from the electrical synapses. We also showed that the space constant of the coupled neurites was 100 microm, approximately twice their length, allowing the efficient spread of synaptic currents all along both coupled neurites. Based on this cytoarchitecture, our main finding was that the degree of electrical coupling modulates the amplitude of EPSPs in the driving neurite by regulating the leak of synaptic current to the coupled neurite, so that the amplitude of EPSPs in the driving neurite was proportional to the value of the coupling resistance. In contrast, synaptic currents arriving at the coupled neurite through the electrical synapse produced EPSPs of constant amplitude. This was because the coupling resistance value had inverse effects on the amount of current arriving and on the impedance of the neurite. We propose that by modulating the amplitude of EPSPs, electrical synapses could regulate the firing frequency of neurons.

Stochastic and deterministic dynamics of intrinsically irregular firing in cortical inhibitory interneurons

Most cortical neurons fire regularly when excited by a constant stimulus. In contrast, irregular-spiking (IS) interneurons are remarkable for the intrinsic variability of their spike timing, which can synchronize amongst IS cells via specific gap junctions. Here, we have studied the biophysical mechanisms of this irregular spiking in mice, and how IS cells fire in the context of synchronous network oscillations. Using patch-clamp recordings, artificial dynamic conductance injection, pharmacological analysis and computational modeling, we show that spike time irregularity is generated by a nonlinear dynamical interaction of voltage-dependent sodium and fast-inactivating potassium channels just below spike threshold, amplifying channel noise. This active irregularity may help IS cells synchronize with each other at gamma range frequencies, while resisting synchronization to lower input frequencies. DOI: http://dx.doi.org/10.7554/eLife.16475.001

The use of human neurons for novel drug discovery in dementia research.

ABSTRACT Introduction: Although many disease models exist for neurodegenerative disease, the translation of basic research findings to clinic is very limited. Studies using freshly resected human brain tissue, commonly discarded from neurosurgical procedures, should complement on-going work using stem cell-derived human neurons and glia thus increasing the likelihood of success in clinical trials. Areas covered: Herein, the authors discuss key issues in the lack of translation from basic research to clinic. They also review the evidence that human neurons, both freshly resected brain tissue and stem cell-derived neurons, such as induced pluripotent stem cells (iPSCs), can be used for analysis of physiological and molecular mechanisms in health and disease. Furthermore, the authors compare and contrast studies using live human brain tissue and studies using induced human stem cell-derived neuron models. Using an example from the area of neurodegeneration, the authors suggest that replicating elements of research findings from animals and stem cell models in resected human brain tissue would strengthen our understanding of disease mechanisms and the therapeutic strategies and aid translation. Expert opinion: The use of human brain tissue alongside iPSC-derived neural models can validate molecular mechanisms identified in rodent disease models and strengthen their relevance to humans. If drug target engagement and mechanism of cellular action can be validated in human brain tissue, this will increase the success rate in clinical research. The combined use of resected human brain tissue, alongside iPSC-derived neural models, could be considered a standard step in pre-clinical research and help to bridge the gap to clinical trials.