mTOR signaling and its roles in normal and abnormal brain development

Target of rapamycin (TOR) was first identified in yeast as a target molecule of rapamycin, an anti-fugal and immunosuppressant macrolide compound. In mammals, its orthologue is called mTOR (mammalian TOR). mTOR is a serine/threonine kinase that converges different extracellular stimuli, such as nutrients and growth factors, and diverges into several biochemical reactions, including translation, autophagy, transcription, and lipid synthesis among others. These biochemical reactions govern cell growth and cause cells to attain an anabolic state. Thus, the disruption of mTOR signaling is implicated in a wide array of diseases such as cancer, diabetes, and obesity. In the central nervous system (CNS), the mTOR signaling cascade is activated by nutrients, neurotrophic factors, and neurotransmitters that enhances protein (and possibly lipid) synthesis and suppresses autophagy. These processes contribute to normal neuronal growth by promoting their differentiation, neurite elongation and branching, and synaptic formation during development. Therefore, disruption of mTOR signaling may cause neuronal degeneration and abnormal neural development. While reduced mTOR signaling is associated with neurodegeneration, excess activation of mTOR signaling causes abnormal development of neurons and glia, leading to brain malformation. In this review, we first introduce the current state of molecular knowledge of mTOR complexes and signaling in general. We then describe mTOR activation in neurons, which leads to translational enhancement, and finally discuss the link between mTOR and normal/abnormal neuronal growth during development.<br/

BDNF is upregulated by postnatal development and visual experience: quantitative and immunohistochemical analyses

PURPOSE. This study sought to elucidate changes in the levels and distribution of brain-derived neurotrophic factor (BDNF) in the retina throughout aging and depending on visual experience. METHODS. Protein and mRNA levels of BDNF were quantified by enzyme-linked immunosorbent assay (ELISA) and semiquantitative reverse transcription-polymerase chain reaction (RT-PCR), respectively. Levels were assayed in the retinas of rats on postnatal day (P)2, P7, and P14 (approximate time of eye opening) and at 1 month (M), 3M, 8M, and 18M of age. Changes in BDNF expression and localization in the retina were assessed by immunohistochemistry. The effect of monocular deprivation during infancy on retinal BDNF expression was also examined, by ELISA and immunohistochemistry. RESULTS. Both protein and mRNA levels of BDNF in the rat retina increased after P14. Immunohistochemical analyses revealed that the increase in BDNF protein levels occurred in retinal ganglion cells (RGCs) between P14 and 1M. BDNF immunoreactivity in Müller cell processes was observed in the inner nuclear layer at 1M, but not at P14. The levels of BDNF protein in the retinas of visually deprived eyes were lower than those of control eyes, as quantified by ELISA. Immunohistochemistry showed that BDNF immunoreactivity in RGCs was diminished by visual deprivation, whereas Müller cells were unaffected. CONCLUSIONS. These observations indicate that BDNF expression in RGCs is upregulated in an activity-dependent manner, whereas that in Müller cells is regulated only by development. (Invest Ophthalmol Vis Sci. 2003;44:3211-3218) DOI: 10.1167/iovs.02-1089 T he neurotrophin family of ligands contains nerve growth factor, brain-derived neurotrophic factor (BDNF), neurotrophin-3, and neurotrophin-4/5. Neurotrophins and their cognate receptors, TrkA, TrkB, and TrkC, are expressed primarily in neurons to mediate pleiotropic effects, promoting the differentiation, maturation, and survival of neurons in both the peripheral and central nervous systems. 1 Accumulating evidence also suggests that neurotrophins affect synaptic functions. 9 Immunocytochemistry of retinal cell culture revealed that BDNF protein was found primarily in RGCs. 16 The high-affinity BDNF receptor TrkB is also present within the retina. 17,18 TrkB mRNA 10 and protein 11 are detectable in the GCL, inner plexiform layer (IPL), and INL. As neurotrophins and their receptors colocalize in the retina, neurotrophins likely act on retinal neurons in an autocrine and/or paracrine manner. 12 It is thought that the expression of BDNF, but not other neurotrophins, is regulated by neural activity. MATERIALS AND METHODS Animals All experimental procedures using animals were performed in accordance with the ARVO Statement for the Use of Animals in Ophthalmic and Vision Research and the institutional guidelines for care and use of laboratory animals. Male Wistar rats (Japan SLC, Hamamatsu, Japan) were housed in standard lighting conditions (12-hour light-dark cycle) for at least 7 days before experimentation. To examine age-related changes in BDNF protein and mRNA levels in the retina, animals were anesthetized by chloral hydrate and killed by decapitation on postnatal From th

Phenotypic Characterization of Transgenic Mice Overexpressing Neuregulin-1

BACKGROUND: Neuregulin-1 (NRG1) is one of the susceptibility genes for schizophrenia and implicated in the neurotrophic regulation of GABAergic and dopaminergic neurons, myelination, and NMDA receptor function. Postmortem studies often indicate a pathologic association of increased NRG1 expression or signaling with this illness. However, the psychobehavioral implication of NRG1 signaling has mainly been investigated using hypomorphic mutant mice for individual NRG1 splice variants. METHODOLOGY/PRINCIPAL FINDINGS: To assess the behavioral impact of hyper NRG1 signaling, we generated and analyzed two independent mouse transgenic (Tg) lines carrying the transgene of green fluorescent protein (GFP)-tagged type-1 NRG1 cDNA. The promoter of elongation-factor 1α gene drove ubiquitous expression of GFP-tagged NRG1 in the whole brain. As compared to control littermates, both heterozygous NRG1-Tg lines showed increased locomotor activity, a nonsignificant trend toward decreasing prepulse inhibition, and decreased context-dependent fear learning but exhibited normal levels of tone-dependent learning. In addition, social interaction scores in both Tg lines were reduced in an isolation-induced resident-intruder test. There were also phenotypic increases in a GABAergic marker (parvalbumin) as well as in myelination markers (myelin basic protein and 2',3'-cyclic nucleotide 3'-phosphodiesterase) in their frontal cortex, indicating the authenticity of NRG1 hyper-signaling, although there were marked decreases in tyrosine hydroxylase levels and dopamine content in the hippocampus. CONCLUSIONS: These findings suggest that aberrant hyper-signals of NRG1 also disrupt various cognitive and behavioral processes. Thus, neuropathological implication of hyper NRG1 signaling in psychiatric diseases should be evaluated with further experimentation

Continuous Measurement of Tissue Oxygen and Carbon Dioxide Gas Tensions in Dog Liver in Ischemia/Reperfusion

An experiment was conducted to determine whether the oxygen and carbon dioxide gas tensions in liver tissue (PtO2 and PtCO2, respectively) reflect the state of microcirculation and/or metabolism in the ischemic liver. Subjects were divided into three groups: group 1, 30 min ischemia; group 2, 60 min ischemia; group 3, four times of intermittent 15 min ischemia after every 10 min of reperfusion. PtO2, PtCO2 and tissue blood flow (TBF) were measured by mass spectrometry, comparatively studied with the serum GOT level as an indicator of liver tissue damage. Furthermore, the time point at which the PtCO2 increase for 1 min initially became less than 1/2 of the maximum value was located on the transit curve of PtCO2, referred to as the critically anaerobic (CA) point, with which new indices of critically anaerobic score (CAS) and time (CAT) (see details in text) were developed. The profiles of PtO2 and PtCO2 during ischemia and reperfusion were clearly demonstrated, and the CA point was observed 12.7 +/- 2.9 min after induction of ischemia. PtO2 was positively correlated with TBF and negatively with the serum GOT level. Furthermore, not only CAS but also CAT were significantly correlated with PtO2, TBF, and the serum GOT level. It was concluded that PtCO2 reflects the state of anaerobic tissue metabolism during ischemia and PtO2 reflects the magnitude of microcirculatory disturbance and tissue injury caused by ischemia/reperfusion. Therefore, continuous monitoring of not only PtO2 but also PtCO2 is beneficial for patients undergoing hepatic surgery with ischemia

Pallidal Hyperdopaminergic Innervation Underlying D2 Receptor-Dependent Behavioral Deficits in the Schizophrenia Animal Model Established by EGF

Epidermal growth factor (EGF) is one of the ErbB receptor ligands implicated in schizophrenia neuropathology as well as in dopaminergic development. Based on the immune inflammatory hypothesis for schizophrenia, neonatal rats are exposed to this cytokine and later develop neurobehavioral abnormality such as prepulse inhibition (PPI) deficit. Here we found that the EGF-treated rats exhibited persistent increases in tyrosine hydroxylase levels and dopamine content in the globus pallidus. Furthermore, pallidal dopamine release was elevated in EGF-treated rats, but normalized by subchronic treatment with risperidone concomitant with amelioration of their PPI deficits. To evaluate pathophysiologic roles of the dopamine abnormality, we administered reserpine bilaterally to the globus pallidus to reduce the local dopamine pool. Reserpine infusion ameliorated PPI deficits of EGF-treated rats without apparent aversive effects on locomotor activity in these rats. We also administered dopamine D1-like and D2-like receptor antagonists (SCH23390 and raclopride) and a D2-like receptor agonist (quinpirole) to the globus pallidus and measured PPI and bar-hang latencies. Raclopride (0.5 and 2.0 µg/site) significantly elevated PPI levels of EGF-treated rats, but SCH23390 (0.5 and 2.0 µg/site) had no effect. The higher dose of raclopride induced catalepsy-like changes in control animals but not in EGF-treated rats. Conversely, local quinpirole administration to EGF-untreated control rats induced PPI deficits and anti-cataleptic behaviors, confirming the pathophysiologic role of the pallidal hyperdopaminergic state. These findings suggest that the pallidal dopaminergic innervation is vulnerable to circulating EGF at perinatal and/or neonatal stages and has strong impact on the D2-like receptor-dependent behavioral deficits relevant to schizophrenia

Perinatal Epidermal Growth Factor Signal Perturbation Results in the Series of Abnormal Auditory Oscillations and Responses Relevant to Schizophrenia

Kai R., Namba H., Sotoyama H., et al. Perinatal Epidermal Growth Factor Signal Perturbation Results in the Series of Abnormal Auditory Oscillations and Responses Relevant to Schizophrenia. Schizophrenia Bulletin Open 2, sgaa070 (2021); https://doi.org/10.1093/schizbullopen/sgaa070.Auditory neurophysiological responses, such as steady-state responses, event-related potential P300/P3, and phase-Amplitude coupling, are promising translational biomarkers for schizophrenia, but their molecular underpinning is poorly understood. Focusing on ErbB receptor signals that are implicated in both schizophrenia and auditory processing/cognition, we explored the causal biological links between ErbB signals and these auditory traits with an experimental intervention into rats. We peripherally challenged rat pups with one of the amniotic ErbB ligands, epidermal growth factor (EGF), and characterized its consequence on the series of these auditory electrocorticographic measures. Auditory brainstem responses (ABRs) and cortical ON responses were also assessed under anesthesia to estimate the influence of higher brain regions. An auditory steady-state paradigm revealed attenuation of spectral power and phase synchrony to 40-Hz stimuli in EGF-challenged rats. We observed a reduction in duration mismatch negativity-like potentials and a delay of P3a responses, all of which are relevant to the reported auditory pathophysiological traits of patients with schizophrenia. Moreover, the perinatal EGF challenges resulted in enhanced theta-Alpha/beta and theta-gamma coupling within the auditory cortex and changes in ABRs. However, the EGF challenges retained the normal ranges of cortical ON responses, potentially ruling out their fundamental auditory deficits. Perinatal exposure of an ErbB ligand to rats strikingly reproduced the whole series of aberrant auditory responses and oscillations previously reported in patients with schizophrenia. Accordingly, these findings suggest that developmental deficits in ErbB/EGF signaling might be involved in the auditory pathophysiology associated with schizophrenia

ErbB2 Dephosphorylation and Anti-Proliferative Effects of Neuregulin-1 in ErbB2-Overexpressing Cells; Re-evaluation of Their Low-Affinity Interaction

Neuregulin-1 binds to ErbB3 and ErbB4 and regulates cancer proliferation and differentiation. Neuregulin-1 had been suggested to also react with ErbB2, but this argument becomes controversial. Here, we re-evaluated the cellular responses and ErbB2 interaction of neuregulin-1 in ErbB2 overexpressing cell lines. In a competitive ligand-binding assay, we detected significant replacement of [35S]-labeled neuregulin-1 with nano molar ranges of cold neuregulin-1 in L929 cells expressing ErbB2 alone and SKOV3 cells carrying sulf-1 cDNA but not in these parental cells. The concentration of neuregulin-1 significantly decreased thymidine incorporation and phosphorylation of ErbB2 (Tyr877, Tyr1396, and Tyr1121) in ErbB2-overexpressing cancer cells as well as in L929 cells expressing ErbB2. A crosslinking assay ascertained the presence of neuregulin-1 immunoreactivity in the ErbB2 immune complexes of L929 expressing ErbB2 alone. These results suggest that the higher concentrations of neuregulin-1 exert an anti-oncogenic activity to attenuate ErbB2 auto-phosphorylation potentially through its low-affinity interaction with ErbB2

Efficacy of Percutaneous Transluminal Coronary Recannalization for Preservation of the Post-Infarct Left Ventricular Regional Wall Motion: A Trial of the Evaluation by Weight­ing Coronary Artery Segments

Efficacy of the percutaneous transluminal coronary recannalization (PTCR) therapy was evaluated by weighting infarct-related coronary artery segments in 28 consecutive patients with acute myocardial infarction. The study focused on the influences of the time interval from the onset of chest pain to PTCR (PTCR-Time) and on the post-infarct left ventricular regional wall motion in conjunction with the serum levels of GOT, LDH and CPK and with PTCR-Time. PTCR success rate was 84.0%, and re-occlusion rate was 4.0%. The thrombolysis in myocardial infarction grade 2, however, was observed in 7 (33.3%) of 21 cases with successful PTCR. There was no significant difference in PTCR-Time between the PTCR success and nonsuccess groups. Significant correlations were observed between the PTCR-Time and each peak value of standardized serum levels of LDH and CPK, and between the PTCR-Time and the post-infarct regional wall motion abnormality. There were also significant correlations between the standardized serum level of each of these three enzymes and the post-infarct regional wall motion abnormality. It was clearly demonstrated that the earlier the recannalization of the infarcted artery was achieved, the less extensive the myocardial damage in quantitative and qualitative aspects.</p