Postnatal development of NR1, NR2A and NR2B immunoreactivity in the visual cortex of the rat

N-Methyl-D-aspartate receptors (NMDARs) are critically involved in some types of synaptic plasticity. The NMDAR subunits NR1, NR2A and NR2B are developmentally regulated, and it has been proposed that developmental changes in their expression may underlie developmental changes in cortical plasticity. Age-dependent change in cortical plasticity is most commonly measured by the monocular deprivation effect, which occurs during a critical period between P22 and P50 in the rat. Although the development of NMDAR subunits has been studied from birth through the fourth postnatal week, there is only meager information from older ages when visual plasticity ends. We hypothesized that there will be significant age-dependent change in expression of NR1, NR2A or NR2B between P22, when the cortex is plastic, and P90, when it is not. We applied specific antibodies recognizing NR1, NR2A and NR2B to the primary visual cortex at P14, P22, P30, P45 and P90. We found age-dependent changes in NR1-IR that were negatively correlated with changes in NR2A-IR; these subunits are not regulated in unison. In contrast, NR2A-IR and NR2B-IR were positively correlated. NR2A-IR and NR2B-IR both passed through a developmental minimum around P45, then recovered to approximately their P22 level. NR1-IR passed through a maximum at P45. There were no significant differences between P22 and P90. These results do not support the simple hypothesis that the loss of plasticity corresponds to a simple transition from juvenile levels of NMDAR subunit proteins to new adult levels. On the other hand, the results do confirm the hypothesis that there are significant changes in processing of NMDAR proteins during the time that plasticity is lost. How these changes of IR relate to synaptic transmission and plasticity needs to be clarified.     

Cocaine facilitates protein synthesis-dependent LTP: The role of metabotropic glutamate receptors

Cocaine addiction alters synaptic plasticity in many brain areas involved in learning and memory processes, including the hippocampus. Long-term potentiation (LTP) is one of the best studied examples of hippocampal synaptic plasticity and it is considered as one of the molecular basis of learning and memory. We previously demonstrated that in the presence of cocaine, a long lasting form of hippocampal LTP is induced by a single pulse of high frequency stimulation, which in normal conditions evokes only an early form of LTP. In this study, we further explore the molecular basis of this modulation of synaptic plasticity by cocaine. By performing pharmacological experiments on hippocampal slices, we were able to show that cocaine converts early LTP to a form of LTP dependent on protein synthesis, probably through the cAMP-dependent protein kinase and extracellular signal-regulated kinase signaling cascades. We also found that metabotropic glutamate receptors are involved in this phenomenon. These studies further clarify the molecular machinery used by cocaine to alter synaptic plasticity and modulate learning and memory processes.     

Expression profiles of hippocampal regenerative sprouting-related genes and their regulation by E-64d in a developmental rat model of penicillin-induced recurrent epilepticus

E-64d (a calpain and autophagy inhibitor) has previously been shown safe for the treatment of Alzheimer's disease in humans. In the present study, the potential protective mechanism of E-64d on hippocampal aberrant mossy fiber sprouting was examined in a developmental rat model of penicillin-induced recurrent epilepticus. A seizure was induced by penicillin every other day in Sprague–Dawley rats from postnatal day 21 (P21). The rats were randomly assigned into the control group (CONT1), the control plus E-64d (CONT2), the seizure group (EXP1) and the seizure plus E-64d (EXP2). On P51, mossy fiber sprouting and related gene expression in hippocampus were assessed by Timm staining and real-time RT-PCR methods, respectively. To validate the RT-PCR results, western blot analysis was performed on selected genes. E-64d obviously suppressed the aberrant mossy fiber sprouting in the supragranular region of dentate gyrus and CA3 subfield of hippocampus. Among the total twelve genes, six genes were strongly up- (MT-3, ACAT1, clusterin and ApoE) or down- (ZnT-1 and PRG-3) regulated by developmental seizures (EXP1) compared with that in the CONT1. Up-regulation of ApoE and Clusterin was blocked by pretreatment with E-64d both in mRNA and protein levels. Further, E-64d-pretreated seizure rats (EXP2) showed a significant downregulation of mRNA expression of PRG-1, PRG-3 and PRG-5, cathepsin B and ApoE, as well as up-regulated nSMase and ANX7 in hippocampus when compared with EXP1 rats. The results of the present study suggest that E-64d, an elective inhibitor of calpain and autophagy, is potentially useful in the treatment of developmental seizure-induced brain damage both by regulating abnormal zinc signal transduction and through the modulation of altered lipid metabolism via ApoE/clusterin pathway in hippocampus.     

Cortical mechanisms underlying variability in intermittent theta-burst stimulation-induced plasticity: A TMS-EEG study

ObjectiveTo test the hypothesis that intermittent theta burst stimulation (iTBS) variability depends on the ability to engage specific neurons in the primary motor cortex (M1).MethodsIn a sham-controlled interventional study on 31 healthy volunteers, we used concomitant transcranial magnetic stimulation (TMS) and electroencephalography (EEG). We compared baseline motor evoked potentials (MEPs), M1 iTBS-evoked EEG oscillations, and resting-state EEG (rsEEG) between subjects who did and did not show MEP facilitation following iTBS. We also investigated whether baseline MEP and iTBS-evoked EEG oscillations could explain inter and intraindividual variability in iTBS aftereffects.ResultsThe facilitation group had smaller baseline MEPs than the no-facilitation group and showed more iTBS-evoked EEG oscillation synchronization in the alpha and beta frequency bands. Resting-state EEG power was similar between groups and iTBS had a similar non-significant effect on rsEEG in both groups. Baseline MEP amplitude and beta iTBS-evoked EEG oscillation power explained both inter and intraindividual variability in MEP modulation following iTBS.ConclusionsThe results show that variability in iTBS-associated plasticity depends on baseline corticospinal excitability and on the ability of iTBS to engage M1 beta oscillations.SignificanceThese observations can be used to optimize iTBS investigational and therapeutic applications.     

The Sensational Hand: Clinical Assessment after Nerve Repair

Following the transection and repair of major nerve trunks in the forearm, the functional outcome is influenced by mechanisms in the peripheral, as well as in the central nervous system. In the present thesis the interest is focused on assessment of the outcome after nerve repair, central nervous factors influencing the outcome, and sense substitution to compensate for sensory loss. A new model instrument for routine documentation of the outcome after repair of a peripheral nerve is identified. The model includes assessments reflecting sensory, motor and pain/discomfort domains. Investigations of frequently used assessment instruments led to the construction and evaluation of a new test instrument for assessment of discriminative sensibility (tactile gnosis) to fit in the model. The summarised outcome, calculated from the model instrument and with a numerical scoring system, conforms well with the patient's opinion on the influence on activities of daily living resulting from the nerve injury, and demonstrates good reliability and validity. A reference interval for the outcome is presented, with the estimated 95% predicted values for the outcome up to five years after the nerve repair. Brain plasticity is a factor sensibility - tactile gnosis - in the adaptive process after a nerve injury, when the mind has to interpret new signal patterns, when objects are touched. For better understanding of the sensory outcome after nerve repair, central nervous factors were examined. Specific cognitive capacities, such as verbal learning and visuo-spatial logic capacity could be identified as being of importance for recovery of tactile gnosis. For patients with temporary or permanent sensory loss, a new principle for artificial sensibility based on sense substitution is presented. The hearing sense substitutes the sense of touch. The resemblance in perceptual experience between sound and touch is bridged by the stereophonic friction sound generated by touching objects, which is then amplified and transmitted to earphones. The delicate capacity of the sense of hearing to discriminate between the complex pattern of frequencies makes it reasonable to assume that hearing is able to take over functions normally devoted to touch. This is demonstrated in the thesis.     

Participation of interleukin 17A in neuroimmune interactions

Inflammation involving the helper T cell 17 (Th17) subset of lymphocytes has been implicated in a number of diseases that affect the nervous system. As the canonical cytokine of Th17 cells, interleukin 17A (IL-17A) is thought to contribute to these neuroimmune interactions. The main receptor for IL-17A is expressed in many neural tissues. IL-17A has direct effects on neurons but can also impact neural function via signaling to satellite cells and immune cells. In the central nervous system, IL-17A has been associated with neuropathology in multiple sclerosis, epilepsy syndromes and ischemic brain injury. Effects of IL-17A at the level of dorsal root ganglia and the spinal cord may contribute to enhanced nociception during neuropathic and inflammatory pain. Finally, IL-17A plays a role in sympathetic axon growth and regeneration of damaged axons that innervate the cornea. Given the widespread effects of IL-17A on neural tissues, it will be important to determine whether selectively mitigating the damaging effects of this cytokine while augmenting its beneficial effects is a possible strategy to treat inflammatory damage to the nervous system.     

Transcranial magnetic stimulation and subjective tinnitus. A review of the literature, 2014–2016

Subjective tinnitus is a symptom in many ENT pathologies, for which there is no curative treatment. It may be poorly tolerated by some patients, who develop attention or sleep disorder or even major anxiety and depression, severely impairing quality of life. Pathophysiological models of the genesis and maintenance of tinnitus symptomatology highlight maladaptive cerebral plasticity induced by peripheral hearing loss. Although not fully elucidated, these changes in neuronal activity are the target of various attempts at neuromodulation, particularly using repetitive transcranial magnetic stimulation (rTMS), which has been the focus of various clinical studies and meta-analyses. A recent consensus statement (Lefaucheur, 2014) reported level-C evidence (possible efficacy) for rTMS using low frequency (1 Hz) tonic stimulation targeting the left cerebral cortex. However, many questions remain concerning the use of this technique in everyday practice. The present article reports a recent literature review using the search-terms “tinnitus” and “rTMS” in the PubMed and Cochrane databases for April 2014 to December 2016.     

Adenosine metabolism of human mesenchymal stromal cells isolated from patients with head and neck squamous cell carcinoma

BackgroundMesenchymal stromal cells (MSC) are a major component of the tumor microenvironment in patients with head and neck squamous cell carcinoma (HNSCC). MSC display innate and regulatory immunologic functions, very similar to many hematopoietic ‘classical’ immune cells. Conversion of ATP to immunosuppressive adenosine is an immunosuppressive mechanism utilized by other hematopoietic immune cells. The present study explores the adenosine metabolism of tumor derived MSC in comparison to autologous MSC from non-malignant tissue.MethodsFrom HNSCC patients (n = 10), paired MSC were generated from tumor tissue (tMSC) and autologous healthy control tissue (cMSC). Differentiation properties and phenotype (CD105, CD73, CD39, CD90, CD26, CD29) were compared by flow cytometry. Production of immunosuppressive adenosine (ADO) by functionally active ectonucleotidases, CD39 and CD73, was determined by luminescence and mass spectrometry. Suppressive activity of ADO was tested in CFSE proliferation assays of isolated T-cells. Plasticity of cMSC was explored after incubation with tumor-cell conditioned media.ResultsDifferentiation into osteogenic, chondrogenic and adipogenic directions was comparable in tMSC and cMSC. Expression of ectonucleotidases, CD39 and CD73, was decreased in tMSC as compared to corresponding cMSC, which correlated with decreased ATP metabolism in mass spectrometry. Proliferation of CD4⁺ T-cells was significantly suppressed by exogenous ADO. Tumor-conditioned medium was unable to down-regulate ADO production in cMSC.ConclusionWe identified MSC of the oropharyngeal mucosa as an important producer of exogenous ADO. In patients with HNSCC, reduced expression of ADO may contribute to excessive inflammation and tumor growth.     

Elevated IGF2 prevents leptin induction and terminal adipocyte differentiation in hemangioma stem cells

Infantile hemangioma is a benign vascular tumor that exhibits a unique yet predictable lifecycle of rapid proliferation followed by spontaneous regression. Recent studies have identified that insulin-like growth factor-2 (IGF2), a fetal mitogen, is highly expressed during the proliferative phase of hemangioma growth. Since hemangiomas arise from CD133 + stem cells, high levels of IGF2 may regulate the activity of the stem cells and therefore, hemangioma growth. The aim of this study was to understand the functional significance of elevated IGF2 in hemangiomas. We show that IGF2 localizes to the CD133 + cells in hemangioma specimens. We, therefore, hypothesized that IGF2 may be regulating the plasticity of hemangioma stem cells. To test our hypothesis, we used CD133-selected cells from hemangiomas to knockdown the expression of IGF2. We found that IGF2 is a mitogen for hemangioma stem cells and prevents leptin induction and full terminal differentiation of hemangioma stem cells into adipocytes. We also show that IGF2 does not alter the initial commitment phase. These findings implicate an important role of IGF2 in expanding hemangioma stem cells and preventing terminal adipocyte differentiation.