Volume 4, Issue 1

Spinal muscular atrophy (SMA) is the leading genetic cause of infant mortality. SMA results from deletions or mutations of survival motor neuron 1 (SMN1), an essential gene. SMN2, a nearly identical copy, can compensate for SMN1 loss if SMN2 exon 7 skipping is prevented. Among the many cis-elements involved in the splicing regulation of SMN exon 7, intronic splicing silencer N1 (ISS-N1) has emerged as the most effective target for an antisense oligonucleotide (ASO)-mediated splicing correction of SMN2 exon 7. Blocking of ISS-N1 by an ASO has been shown to fully restore SMN2 exon 7 inclusion in SMA patient cells as well as in vivo. Here we review how ISS-N1 targeting ASOs that use different chemistries respond differently in the various SMA mouse models. We also compare other ASO-based strategies for therapeutic splicing correction in SMA. Given that substantial progress on ASO-based strategies to promote SMN2 exon 7 inclusion in SMA has been made, and that similar approaches in a growing number of genetic diseases are possible, this report has wide implications.

Transgenic mouse models with knock-in (KI) expression of human mutant amyloid precursor protein (APP) and/or human presenilin 1 (PS1) may be helpful to elucidate the cellular consequences of APP and PS1 misprocessing in the aging brain. Age-related alterations in total numbers of neurons and in numbers of synaptophysin-immunoreactive presynaptic boutons (SIPB), as well as the amyloid plaque load were analyzed in the hippocampal dentate gyrus (DG), CA3, and CA1-2 of 2- and 10-month-old APPSL/PS1 homozygous KI, APPSL (expressing human mutant APP751 carrying the Swedish [K670N/M671L] and London [V717I] mutations under Thy-1 promoter), and PS1 homozygous KI mice (expressing human PS1 mutations [M233T and L235P]). APPSL/PS1 homozygous KI mice, but neither APPSL mice nor PS1 homozygous KI mice, showed substantial agerelated loss of neurons (−47.2%) and SIPB (−22.6%), specifically in CA1-2. PS1 homozygous KI mice showed an age-related increase in hippocampal granule cell numbers (+37.9%). Loss of neurons and SIPB greatly exceeded the amount of local extracellular Aβ aggregation and astrocytes, whereas region-specific accumulation of intraneuronal Aβ preceded neuron and synapse loss. An age-related increase in the ratio of SIPB to neuron numbers in CA1-2 of APPSL/PS1 homozygous KI mice was suggestive of compensatory synaptic plasticity. These findings indicate a region-selectivity in intra- and extraneuronal Aβ accumulation in connection with neuron and synapse loss in the hippocampus of APPSL/PS1 homozygous KI mice.

Transcranial electrical stimulation (TES) includes methods such as transcranial direct current stimulation, transcranial random noise stimulation, and transcranial alternating current stimulation. These methods provide novel ways of enhancing human cognitive abilities for restorative purposes, or for general cognitive enhancement, by modulating neuronal activity. I discuss here the basic principles behind these methods and provide some illustrations of their efficacy in cognitive enhancement in those with typical and atypical brain function. Next, I outline some future directions for research that are have been largely neglected, such as the issue of individual differences, cognitive side effects, the efficacy of TES for use with healthy elderly populations, children with atypical development, and sports. The results observed thus far with TES as well as its future possibilities have significant implications for both basic and translational neuroscience.

Olfaction is frequently mentioned as a “neglected sense”, although the olfactory system has several interesting and unique anatomical and physiological features. Olfactory involvement is present in several degenerative disorders, especially in Alzheimer’s disease (AD). The peripheral and central parts of the olfactory system are damaged even in the early stages of AD, manifesting in profound olfactory deficits. Besides the early pathology, the olfactory system may be involved in the pathogenesis of AD by providing a route of entry for pathological agents still unknown. In contrast to this olfactory vector hypothesis, the olfactory system can be used to deliver therapeutic agents in AD, such as nerve growth factor and insulin, by decreasing the side-effects of the therapy or providing a non-invasive method of delivery.

Neurotrophins and other growth factors have been advanced as critical modulators of depressive behavior. Support for this model is based on analyses of knockout and transgenic mouse models, human genetic studies, and screens for gene products that are regulated by depressive behavior and/or antidepressants. Even subtle alteration in the regulated secretion of brain-derived neurotrophic factor (BDNF), for example, due to a single nucleotide polymorphism (SNP)-encoded Val-Met substitution in proBDNF that affects processing and sorting, impacts behavior and cognition. Alterations in growth factor expression result in changes in neurogenesis as well as structural changes in neuronal cytoarchitecture, including effects on dendritic length and spine density, in the hippocampus, nucleus accumbens, and prefrontal cortex. These changes have the potential to impact the plasticity and stability of synapses in the CNS, and the complex brain circuitry that regulates behavior. Here we review the role that neurotrophins play in the modulation of depressive behavior, and the downstream signaling targets they regulate that potentially mediate these behavioral pro-depressant and antidepressant effects.

Diffusion-based MR imaging is the only non-invasive method for characterising the microstructural organization of brain tissue in vivo. Diffusion tensor MRI (DT-MRI) is currently routinely used in both research and clinical practice. However, other diffusion approaches are gaining more and more popularity and an increasing number of researchers express interest in using them concomitantly with DT-MRI. While non tensor-based methods hold great promises for increasing the specificity of diffusion MR imaging, including them in the experimental routine inevitably leads to longer experimental times. In most cases, this may preclude the translation of the full protocol to clinical practice, especially when these methods are to be used with subjects that are not compatible with long scanning sessions (e.g., with elderly and pediatric subjects who have difficulties in maintaining a fixed head position during a long imaging session). The aim of this review is to guide the end-users on obtaining the maximum from the experimental time allocated to collecting diffusion MRI data. This is done by: (i) briefly reviewing non tensor-based approaches; (ii) reviewing the optimal protocols for both tensor and non tensor-based imaging; and (iii) drawing the conclusions for different experimental times.

The Gq-linked G protein coupled receptors (GPCRs) and their signaling pathways are important clinical targets for the dementia of Alzheimer’s disease and cognitive decline with aging. Gq stimulates phospholipase C-β1 (PLC-β1) activity, increasing levels of inositol-1, 4, 5-trisphosphate (IP3) and diacylglycerol, to initiate mobilization of intracellular Ca2+ and activation of protein kinase C, respectively. While high concentrations of ligand typically evoke large sustained increases in cytosolic Ca2+ levels, it has long been appreciated that the dynamics of the Ca2+ increase are more complex and consistent with multiple levels of regulation. Physiologically relevant concentrations of Gq-ligands evoke rhythmic fluctuations or an oscillation in the level of cytosolic Ca2+. Downstream targets are tuned to respond to the frequency of the Ca2+ oscillations which in turn, reflect the oscillations in IP3 levels. Oscillatory behavior depends on the assembly of self-organizing interactions. The components that contribute to and regulate the Ca2+ oscillator have been unclear, precluding transfer of this fundamental knowledge from bench to bedside. Many GPCRs that signal with Gq also co-signal with G12. G protein co-signaling could therefore regulate the Ca2+ oscillator. This letter explores the potential relationship between Ca2+ oscillations, G protein co-signaling and cellular response in the context of our recent observations. We found that Gq efficacy is synergistic with phosphatidic acid, (PA), a signaling mediator generated downstream of activated G12 and RhoA. Regulation by PA depends on interaction with the unique PLC-β1 PA binding region. G protein co-signaling is therefore a mechanism for GPCRs to collectively assemble self-organizing interactions that regulate the Ca2+ oscillator.

The neuropeptide somatostatin (SST) is an important modulator of neurotransmission in the central nervous system (CNS) and binds to G-protein-coupled receptors (SSTR1-5) on target cells. Little is known about the expression and function of the somatostatinergic system in the mammalian cochlea. We analyzed the expression of SSTR1-SSTR5 in the immature mammalian cochlea. The peak in the expression of SSTR1 and SSTR2 at mRNA and protein level is around the onset of hearing to airborne sound, at postnatal day (P)14. This suggests their involvement in the maturation of the mammalian cochlea. We demonstrated that all five receptors are expressed in the inner hair cells (IHC) and outer hear cells (OHC) as well as in defined supporting cells of the organ of Corti (OC) in the adult mouse cochlea. A similar expression of the SSTRs in the IHC and OHC was found in cultivated P6 mouse OC explants as well as in neuroepithelial cell culture. In order to learn more about the regulation of SSTRs, we used mice with either a deletion of SSTR1, SSTR2 or SSTR1/SSTR2 double knock out (DKO). In DKO mice, SSTR5 was up-regulated and SSTR3 and SSTR4 were down regulated. These findings provide evidence of a compensatory regulation in the mammalian cochlea as a consequence of a receptor subtype deletion. In addition, we observed reduced levels of phospho-Akt and total-Akt in SSTR1 KO and DKO mice as compared to wild type (WT) mice. Akt is likely to be involved in hair cell survival. Most importantly, we found improved hair cell survival in somatostatin and octreotide treated OC explants that had been exposed to gentamicin compared to those explants exposed to gentamicin alone. These findings propose that the somatostatinergic system within the cochlea may have neuroprotective properties.

Science has shown that risk of cavitation and hyperthermia following prenatal ultrasound exposure is relatively negligible provided intensity, frequency, duration of exposure, and total numbers of exposures are safely limited. However, noncavitational mechanisms have been poorly studied and occur within what are currently considered “safe” levels of exposure. To date, the teratogenic capacity of noncavitational effectors are largely unknown, although studies have shown that different forms of ultrasound-induced hydraulic forces and pressures can alter membrane fluidity, proliferation, and expression of inflammatory and repair markers. Loose regulations, poor end user training, and unreliable ultrasound equipment may also increase the likelihood of cavitation and hyperthermia during prenatal exposure with prolonged durations and increased intensities. The literature suggests a need for tighter regulations on the use of ultrasound and further studies into its teratogenicity.

The Spanish histologist Santiago Ramón y Cajal and the Italian anatomist Camillo Golgi, who were jointly awarded the 1906 Nobel Prize in Physiology or Medicine for their discoveries on the structure of the nervous system, are two of the most notable figures in neuroscience. It was the’ Golgi method’ that enabled Cajal to gather evidence and defend neuronism (the contiguity of neurons as independent cellular units) against his chief rival’s reticularism (the intracellular continuity of the cytoplasm among neurons in a widespread reticulum). Seven months after his Nobel lecture in Stockholm, Cajal wrote a powerful article which he titled’ El renacimiento de la doctrina neuronal’ (the rebirth, revival, or renaissance of the neuron doctrine) as a response to an insurrection of reticularist ideas. This new wave of reticularism was instigated in Spain by the pathologist Eduardo García Solá, Rector of the University of Granada at the time, and stemmed from the interpretation of nerve regeneration experiments conducted by the German physiologist Albrecht von Bethe in Strassburg (today Strasbourg, France) and the Hungarian histologist Stephan von Apáthy in Kolozsvár (today Cluj-Napoca, Romania). Cajal’s article was hosted by four different journals (three in Spain and one in Argentina). It constitutes an important testimony for the history of the neuron theory that has gone unheeded thus far. Therefore, we provide an English translation of Cajal’s Spanish paper, placing it in the context of evolving notions during that first decade of the twentieth century crucial for neurobiology.