Spine head calcium as a measure of summed postsynaptic activity for driving synaptic plasticity

We use a computational model of a hippocampal CA1 pyramidal cell to demonstrate that spine head calcium provides an instantaneous readout at each synapse of the postsynaptic weighted sum of all presynaptic activity impinging on the cell. The form of the readout is equivalent to the functions of weighted, summed inputs used in neural network learning rules. Within a dendritic layer, peak spine head calcium levels are either a linear or sigmoidal function of the number of coactive synapses, with nonlinearity depending on the ability of voltage spread in the dendrites to reach calcium spike threshold. This is strongly controlled by the potassium A-type current, with calcium spikes and the consequent sigmoidal increase in peak spine head calcium present only when the A-channel density is low. Other membrane characteristics influence the gain of the relationship between peak calcium and the number of active synapses. In particular, increasing spine neck resistance increases the gain due to increased voltage responses to synaptic input in spine heads. Colocation of stimulated synapses on a single dendritic branch also increases the gain of the response. Input pathways cooperate: CA3 inputs to the proximal apical dendrites can strongly amplify peak calcium levels due to weak EC input to the distal dendrites, but not so strongly vice versa. CA3 inputs to the basal dendrites can boost calcium levels in the proximal apical dendrites, but the relative electrical compactness of the basal dendrites results in the reverse effect being less significant. These results give pointers as to how to better describe the contributions of pre- and postsynaptic activity in the learning "rules" that apply in these cells. The calcium signal is closer in form to the activity measures used in traditional neural network learning rules than to the spike times used in spike-timing-dependent plasticity.Output Type: Lette

Gait analysis in a <i>Mecp2</i> knockout mouse model of Rett syndrome reveals early-onset and progressive motor deficits

Rett syndrome (RTT) is a genetic disorder characterized by a range of features including cognitive impairment, gait abnormalities and a reduction in purposeful hand skills. Mice harbouring knockout mutations in the &lt;i&gt;Mecp2&lt;/i&gt; gene display many RTT-like characteristics and are central to efforts to find novel therapies for the disorder. As hand stereotypies and gait abnormalities constitute major diagnostic criteria in RTT, it is clear that motor and gait-related phenotypes will be of importance in assessing preclinical therapeutic outcomes. We therefore aimed to assess gait properties over the prodromal phase in a functional knockout mouse model of RTT. In male &lt;i&gt;Mecp2&lt;/i&gt; knockout mice, we observed alterations in stride, coordination and balance parameters at 4 weeks of age, before the onset of other overt phenotypic changes as revealed by observational scoring. These data suggest that gait measures may be used as a robust and early marker of &lt;i&gt;Mecp2&lt;/i&gt;-dysfunction in future preclinical therapeutic studies

Reduced axonal diameter of peripheral nerve fibres in a mouse model of Rett syndrome

Rett syndrome (RTT) is a neurological disorder characterized by motor and cognitive impairment, autonomic dysfunction and a loss of purposeful hand skills. In the majority of cases, typical RTT is caused by de novo mutations in the X-linked gene, MECP2. Alterations in the structure and function of neurons within the central nervous system of RTT patients and Mecp2-null mouse models are well established. In contrast, few studies have investigated the effects of MeCP2-deficiency on peripheral nerves. In this study, we conducted detailed morphometric as well as functional analysis of the sciatic nerves of symptomatic adult female Mecp2+/- mice. We observed a significant reduction in the mean diameter of myelinated nerve fibers in Mecp2+/- mice. In myelinated fibers, mitochondrial densities per unit area of axoplasm were significantly altered in Mecp2+/- mice. However, conduction properties of the sciatic nerve of Mecp2 knockout mice were not different from control. These subtle changes in myelinated peripheral nerve fibers in heterozygous Mecp2 knockout mice could potentially explain some RTT phenotypes

Biomechanical properties of bone in a mouse model of Rett syndrome

Rett syndrome (RTT) is an X-linked genetic disorder and a major cause of intellectual disability in girls. Mutations in the methyl-CpG binding protein 2 (&lt;i&gt;MECP2&lt;/i&gt;) gene are the primary cause of the disorder. Despite the dominant neurological phenotypes, &lt;i&gt;MECP2&lt;/i&gt; is expressed ubiquitously throughout the body and a number of peripheral phenotypes such as scoliosis, reduced bone mineral density and skeletal fractures are also common and important clinical features of the disorder. In order to explore whether MeCP2 protein deficiency results in altered structural and functional properties of bone and to test the potential reversibility of any defects, we have conducted a series of histological, imaging and biomechanical tests of bone in a functional knockout mouse model of RTT. Both hemizygous &lt;i&gt;Mecp2&lt;/i&gt;&lt;sup&gt;stop/y&lt;/sup&gt; male mice in which &lt;i&gt;Mecp2&lt;/i&gt; is silenced in all cells and female &lt;i&gt;Mecp2&lt;/i&gt;&lt;sup&gt;stop/+&lt;/sup&gt; mice in which &lt;i&gt;Mecp2&lt;/i&gt; is silenced in ~ 50% of cells as a consequence of random X-chromosome inactivation, revealed significant reductions in cortical bone stiffness, microhardness and tensile modulus. Microstructural analysis also revealed alterations in both cortical and cancellous femoral bone between wild-type and MeCP2-deficient mice. Furthermore, unsilencing of &lt;i&gt;Mecp2&lt;/i&gt; in adult mice cre-mediated stop cassette deletion resulted in a restoration of biomechanical properties (stiffness, microhardness) towards wild-type levels. These results show that MeCP2-deficiency results in overt, but potentially reversible, alterations in the biomechanical integrity of bone and highlights the importance of targeting skeletal phenotypes in considering the development of pharmacological and gene-based therapies

Differential Dependence of GABAergic and Glutamatergic Neurons on Glia for the Establishment of Synaptic Transmission

In the mammalian cortex, GABAergic and glutamatergic neurons represent 2 major neuronal classes, which establish inhibitory and excitatory synapses, respectively. Despite differences in their anatomy, physiology and developmental origin, both cell types require support from glial cells, particularly astrocytes, for their growth and survival. Recent experiments indicate that glutamatergic neurons also depend on astrocytes for synapse formation. However, it is not clear if the same holds true for GABAergic neurons. By studying highly pure GABAergic cell cultures, established through fluorescent activated cell sorting, we find that purified GABAergic neurons are smaller and have reduced survival, nevertheless they establish robust synaptic transmission in the absence of glia. Support from glial cells reverses morphological and survival deficits, but does little to alter synaptic transmission. In contrast, in cultures of purified glutamatergic neurons, morphological development, survival and synaptic transmission are collectively dependent on glial support. Thus, our results demonstrate a fundamental difference in the way GABAergic and glutamatergic neurons depend on glia for the establishment of synaptic transmission, a finding that has important implications for our understanding of how neuronal networks develop

Label-free imaging of thick tissue at 1550nm using a femtosecond optical parametric generator

We have developed a simple wavelength tunable optical parametric generator (OPG), emitting broad band ultrashort pulses with peak wavelengths at 1530-1790 nm, for nonlinear label-free microscopy. The OPG consists of a periodically poled lithium niobate crystal, pumped at 1064 nm by a ultrafast Yb:fiber laser with high pulse energy. We demonstrate that this OPG can be used for label-free imaging, by third harmonic generation, of nuclei of brain cells and blood vessels in a >150 µm thick brain tissue section, with very little decay of intensity with imaging depth and no visible damage to the tissue at an incident average power of 15 mW

Foot-Ground Reaction Force During Resistance Exercise in Parabolic Flight

An interim Resistance Exercise Device (iRED) was designed to provide resistive exercise as a countermeasure to space flight-induced loss of muscle strength and endurance as well as decreased bone mineral density. The purpose of this project was to compare foot-ground reaction force during iRED exercise in normal gravity (l-g) versus micro gravity (O-g) achieved during parabolic flight. METHODS: Four subjects performed three exercises using the iRED (squat, heel raise, and deadlift) during I-g and O-g at a moderate intensity (60% of maximum strength during deadlift exercise). Foot-ground reaction force was measured in three axes (x,y,z) using a force plate, and the magnitude of the resultant force vector was calculated (r = ~X 2 + y2 + Z2 ). Range of motion (ROM) was measured using a linear encoder. Peak force (PkF) and total work (TW) were calculated using a customized computer program. Paired t-tests were used to test if significant differences (p.::::0.05) were observed between I-g and O-g exercise. RESULTS: PkF and TW measured in the resultant axis were significantly less in O-g for each of the exercises tested. During O-g, PkF was 42-46% and TW was 33- 37% of that measured during I-g. ROM and average time to complete each repetition were not different from I-g to O-g. CONCLUSIONS: When performing exercises in which body mass is a portion of the resistance during I-g, PkF and TW measured during resistive exercise were reduced approximately 60-70% during O-g. Thus, a resistive exercise device during O-g will be required to provided higher resistances to induce a similar training stimulus to that on Earth

Bio-inspired models of memory capacity, recall performance and theta phase precession

The hippocampus plays an important role in the encoding and retrieval of spatial and non-spatial memories. Much is known about the anatomical, physiological and molecular characteristics as well as the connectivity and synaptic properties of various cell types in the hippocampal circuits [1], but how these detailed properties of individual neurons give rise to the encoding and retrieval of memories remains unclear. Computational models play an instrumental role in providing clues on how these processes may take place. Here, we present three computational models of the region CA1 of the hippocampus at various levels of detail. Issues such as retrieval of memories as a function of cue loading, presentation frequency and learning paradigm, memory capacity, recall performance, and theta phase precession in the presence of dopamine neuromodulation and various types of inhibitory interneurons are addressed. The models lead to a number of experimentally testable predictions that may lead to a better understanding of the biophysical computations in the hippocampus

Inhibition of Piezo1 attenuates demyelination in the central nervous system

Piezo1 is a mechanosensitive ion channel that facilitates the translation of extracellular mechanical cues to intracellular molecular signaling cascades through a process termed, mechanotransduction. In the central nervous system (CNS), mechanically gated ion channels are important regulators of neurodevelopmental processes such as axon guidance, neural stem cell differentiation, and myelination of axons by oligodendrocytes. Here, we present evidence that pharmacologically mediated overactivation of Piezo1 channels negatively regulates CNS myelination. Moreover, we found that the peptide GsMTx4, an antagonist of mechanosensitive cation channels such as Piezo1, is neuroprotective and prevents chemically induced demyelination. In contrast, the positive modulator of Piezo1 channel opening, Yoda‐1, induces demyelination and neuronal damage. Using an ex vivo murine‐derived organotypic cerebellar slice culture model, we demonstrate that GsMTx4 attenuates demyelination induced by the cytotoxic lipid, psychosine. Importantly, we confirmed the potential therapeutic effects of GsMTx4 peptide in vivo by co‐administering it with lysophosphatidylcholine (LPC), via stereotactic injection, into the cerebral cortex of adult mice. GsMTx4 prevented both demyelination and neuronal damage usually caused by the intracortical injection of LPC in vivo; a well‐characterized model of focal demyelination. GsMTx4 also attenuated both LPC‐induced astrocyte toxicity and microglial reactivity within the lesion core. Overall, our data suggest that pharmacological activation of Piezo1 channels induces demyelination and that inhibition of mechanosensitive channels, using GsMTx4, may alleviate the secondary progressive neurodegeneration often present in the latter stages of demyelinating diseases