Neuroscience Letters (NEUROSCI LETT)

Publications in this journal

• Article: α-Synuclein mutations cluster around a putative protein loop.

  Eleanna Kara, Patrick A Lewis, Helen Ling, Christos Proukakis, Henry Houlden, John Hardy
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  ABSTRACT: With the recent identification of two new pathogenic mutations in α-synuclein, we map the five known pathogenic mutations onto the best available models of the protein structure. We show that four of the five mutations map to a potential fold in the protein with the exception being the A30P mutation in which the substitution would be expected to have a profound effect on protein structure. We discuss this localisation in terms of the proposed mechanisms for mutation pathogenicity.
  Neuroscience Letters 05/2013;
• Article: Copper enhances APP dimerization and promotes Aβ production.

  Yasuha Noda, Megumi Asada, Masakazu Kubota, Masato Maesako, Kiwamu Watanabe, Maiko Uemura, Takeshi Kihara, Shun Shimohama, Ryosuke Takahashi, Ayae Kinoshita, Kengo Uemura
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  ABSTRACT: Alzheimer's disease (AD) is characterized by the deposition of amyloid-β (Aβ) plaques, senile plapue. The Aβ peptide is cleaved from amyloid precursor protein (APP) by β-secretase and γ-secretase. Until now, many literatures have documented that the high concentration of copper is present in Aβ plaques and enhances aggregation of. The APP copper binding domain (CuBD) is located in the N-terminal next to the growth factor-like domain that gets involved in APP homodimerization. Importantly, dimerization of APP has profound effect on Aβ production. We investigated whether copper alters the state of APP dimerization and how it affects APP metabolism. Here, we demonstrate that copper enhanced APP dimerization and increased extracellular release of Aβ. Moreover, copper chelator, D-penicillamine, suppressed APP dimerization and decreased extracellular release of Aβ. These results suggest that the action of copper may be profoundly associated with the pathway of Aβ production in AD pathogenesis.
  Neuroscience Letters 05/2013;
• Article: Neurobehavioral Deficits of Epidermal Growth Factor-Overexpressing Transgenic Mice: Impact on Dopamine Metabolism.

  Takeyoshi Eda, Makoto Mizuno, Kazuaki Araki, Yuriko Iwakura, Hisaaki Namba, Hidekazu Sotoyama, Akiyoshi Kakita, Hitoshi Takahashi, Hiroshi Satoh, Siu-Yuen Chan, Hiroyuki Nawa
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  ABSTRACT: Epidermal growth factor (EGF) and its family member neuregulin-1 are implicated in the etiology of schizophrenia. Our recent pharmacological studies indicate that EGF injections to both neonatal and adult rats induce neurobehavioral deficits relevant to schizophrenia. We, however, did not evaluate the genetic impact of EGF transgene on neurobehavioral traits. Here we analyzed transgenic mice carrying the transgene of mouse EGF cDNA. As compared to control littermates, heterozygous EGF transgenic mice had an increase in EGF mRNA levels and showed significant decreases in prepulse inhibition and context-dependent fear learning, but there were no changes in locomotor behaviors and sound startle responses. In addition, these transgenic mice exhibited higher behavioral sensitivity to the repeated cocaine injections. There were neurochemical alterations in metabolic enzymes of dopamine (i.e., tyrosine hydroxylase, dopa decarboxylase, catechol-O-methyl transferase) and monoamine contents in various brain regions of the EGF transgenic mice, but there were no apparent neuropathological signs in the brain. The present findings rule out the indirect influence of anti-EGF antibody production on the behavioral deficits of EGF-injected mice. These results support the argument that aberrant hyper-signals of EGF have significant impact on mouse behavioral traits and dopamine metabolism.
  Neuroscience Letters 05/2013;
• Article: Dynamic Connectivity Laterality of the Amygdala under Negative Stimulus in Depression: a MEG Study.

  Qing Lu, Yi Wang, Guoping Luo, Haoran Li, Zhijian Yao
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  ABSTRACT: Depression is a mental disorder characterized by emotional and cognitive dysfunction, which is related to the abnormal activity in brain regions involving emotion processing such as amygdala (AMYG). The laterality of AMYG during emotional information processing has always been a controversial issue in any depression study, however, the dynamic characteristic of laterality in the AMYG has been ignored. In this paper, we proposed to explore the time-varying functional coupling between the anterior cingulate cortex (ACC) and the bilateral AMYG in the time-frequency domain. As a result, an emotional facial expression paradigm was undertaken in this study. Using magnetoencephalogram (MEG) data acquired from 16 patients with major depression disorder and 16 matched healthy controls, we calculated the wavelet coherence. The research led to the conclusion that, after sad facial stimuli, the ACC-bilateral AMYG connectivity in depressive patients showed a significant decrease in the beta band during the first 100ms. In addition, the ACC-left AMYG connectivity led to a significant increase in the gamma band around 400ms and in beta band around 700ms. Our work suggests a lack of sufficient inhibition of the ACC on the bilateral AMYG in the early period and the lateralized dysregulation of the ACC on the left AMYG in late period during the sad facial information processing task. We hypothesised that the clinical manifestations of depression may partly result from it.
  Neuroscience Letters 05/2013;
• Article: Ectopic hair cell-like cell induction by Math1 mainly involves direct transdifferentiation in neonatal mammalian cochlea.

  Juanmei Yang, Zhao Han, Fanglu Chi, Yibo Huang, Ning Cong
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  ABSTRACT: Math1, also known as Atoh1, is a basic helix-loop-helix transcription factor that plays a key role in hair cells (HCs) development. Previous studies have reported that Math1 gene transfer could induce the production of ectopic hair cell-like cells both in vitro and in vivo. Here, we focused on the mechanism of ectopic hair cell-like cellular differentiation from cells in the lateral epithelial ridge (LER) of cochlea with a human adenovirus serotype 5 (Ad5) vector encoding both Math1 and the reporter gene EGFP. Within the Ad5-EGFP-Math1 infection, hair-cell like cells could be detected in the LER. 5'-bromo-2' deoxyuridine (BrdU) incorporation test results at different time points suggested that LER cells possessed high potential to proliferation, but they could not transdifferentiate into hair cells spontaneously. Almost all of Math1 induced hair cell-like cells were BrdU negative when BrdU incorporation occurred after Math1 expression. In conclusion, Math1 induced hair cell-like cells from LER cells mainly underwent direct trans-differentiation instead of mitosis of LER cells or newly hair cell-like cells.
  Neuroscience Letters 05/2013;
• Article: Pinocembrin protects brain against ischemia/reperfusion injury by attenuating endoplasmic reticulum stress induced apoptosis.

  Cai-Xia Wu, Rui Liu, Mei Gao, Gang Zhao, Song Wu, Chun-Fu Wu, Guan-Hua Du
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  ABSTRACT: Endoplasmic reticulum stress (ER stress) is known to play a vital role in mediating ischemic reperfusion damage in brain. Our previous studies showed that pinocembrin alleviated cerebral ischemic injury in ischemia/reperfusion and vascular dementia animal models, but whether attenuation of ER stress-induced apoptosis contributes to the mechanisms remains to be elucidated. In this study, an attempt was therefore made to investigate the modulation effect of pinocembrin on ischemia/reperfusion-induced ER stress in brain. Focal cerebral ischemia/reperfusion rats were induced by middle cerebral artery occlusion (MCAO) for 2h followed by 6h reperfusion. Pinocembrin was administered in different doses (1mg/kg, 3mg/kg, and 10mg/kg, respectively) at the same time of onset of reperfusion. Neurological function and brain infarction were evaluated. Terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) method, and flow cytometer (FCM) were used to investigate cell apoptosis in penumbra cortex. DNA fragmentation assay was also performed using electrophoresis. The expression of ER stress proteins of GRP78, CHOP/GADD153, ATF4, eIF2α phosphorylation was detected by western blot, and caspase-12 was evaluated by immunohistochemical analysis. Our results demonstrate that pinocembrin-treatment (3mg/kg and 10mg/kg) significantly reduced neurological deficit scores, infarct volume, and neuron apoptosis in the ischemia/reperfusion rats. It can also significantly modulate the protein levels by increasing GRP78 (10mg/kg) and attenuating CHOP/GADD153 expression along with caspase-12 activation (3mg/kg and 10mg/kg). At the same time, eIF2α phosphorylation was restrained and the expression of ATF4 was reduced (3mg/kg and 10mg/kg). These results suggest that the attenuation of ER stress induced apoptosis may be involved in the mechanisms of pinocembrin.
  Neuroscience Letters 05/2013;
• Article: Upregulated acetylcholine synthesis during early differentiation in the embryonic stem cell line CGR8.

  Ignaz Wessler, Rosmarie Michel-Schmidt, Harald Schmidt, Susanne Kaltwasser, Ronald Unger, Charles James Kirkpatrick
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  ABSTRACT: Stem cells are used to generate differentiated somatic cells including neuronal cells. Synthesis and release of acetylcholine, a neurotransmitter and widely expressed signalling molecule, were investigated in the murine embryonic stem cell line CGR8 during early differentiation, i.e. in the presence of leukaemia inhibitory factor (LIF) to maintain pluripotency and in the absence of LIF to induce early differentiation. CGR8 cells express choline acetyltransferase (ChAT) as demonstrated by measurement of enzyme activity and substantial inhibition by bromoacetylcholine. Pluripotent CGR8 cells showed a ChAT activity of 250pmol acetylcholine/mg/h, contained 1.1pmol acetylcholine/10(6) cells and released about 12.00pmol acetylcholine/1×10(6) cells/6h. Removal of LIF induced early differentiation as evidenced by reduced transcription factors Oct-4 and Nanog and a substantial slowing of the proliferation rate. Under this condition acetylcholine synthesis increased to 1640pmol/mg/h; related to the pluripotent state the content of acetylcholine increased 10fold and the release to about32pmol acetylcholine/1×10(6) cells/6h.Enzyme kinetic analysis showed a significant increase of the Km for the precursor acetyl-CoA and of Vmax without a change of the Km for the precursor choline. In conclusion, early differentiation of the stem cell line CGR8 is associated with a substantial increase in ChAT activity and acetylcholine release.
  Neuroscience Letters 05/2013;
• Article: Curcumin promotes nerve regeneration and functional recovery in rat model of nerve crush injury.

  Junxiong Ma, Jun Liu, Hailong Yu, Qi Wang, Yu Chen, Liangbi Xiang
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  ABSTRACT: BACKGROUND AND AIM: Curcumin at 100mg/kg has been shown to have a protective effect on crush nerve injury. However, it is unclear whether the protective effect of curcumin on nerve injury is dose dependent. The present study was designed to investigate such a possibility. METHODS: The rats subjected to crush nerve injury were intraperitoneally administrated daily for 4 weeks with curcumin (50mg/kg, 100mg/kg and 300mg/kg), or 100μg/kg mecobalamin or normal saline, respectively. The axonal regeneration was investigated by retrograde labeling and morphometric analysis. The motor functional recovery was evaluated by electrophysiological studies, behavioral tests and histological appearance of the target muscles. RESULTS: Our data showed that curcumin and mecobalamin achieved better nerve regeneration and functional recovery than vehicle group. In addition, high doses of curcumin (100mg/kg and 300mg/kg) showed better performance in promoting nerve regeneration and functional recovery than low dose of curcumin (50mg/kg). CONCLUSIONS: Curcumin is capable of promoting nerve regeneration after nerve injuries, highlighting the therapeutic values of curcumin as a neuroprotective drug for peripheral nerve repair applications.
  Neuroscience Letters 05/2013;
• Article: Scopolamine modulates paternal parental retrieval behavior in mice induced by the maternal mate.

  Hiroko Fujimoto, Hong-Xiang Liu, Olga Lopatina, David A Brown, Haruhiro Higashida
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  ABSTRACT: Appropriate parental care by the father can greatly facilitate healthy human family life. Much less is known from animal studies about the factors leading to paternal parental care than those favoring maternal parent care. Recently, we have reported that sires of the ICR strain of laboratory mice can express maternal-like retrieval behavior when separated from their pups through ultrasound and pheromonal signals from the dam, i.e. mate-dependent parental care. The sire's retrieval behavior was inhibited by prior treatment of scopolamine, a muscarinic cholinergic inhibitor, and recovered by physostigmine. KCNQ K(+)-channel blocking and enhancing drugs, linopiridine and retigabine, were also examined. Linopiridine alone did not enhance care after pairing with the dam, nor change scopolamine-induced inhibition of care. Retigabine totally suppressed parental care, and this effect was partially rescued by co-administration of linopiridine. These results indicate the involvement of cholinergic cellular signaling in the central nervous system in the maternal induction of paternal parental behavior in ICR mice.
  Neuroscience Letters 05/2013;
• Article: NF-κB activity is inversely correlated to RNF11 expression in Parkinson's disease.

  Elaine Pranski, Carson D Van Sanford, Nirjari Dalal, Adam L Orr, Dipan Karmali, Deborah S Cooper, Marla Gearing, James J Lah, Allan I Levey, Ranjita Betarbet
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  ABSTRACT: RING finger protein 11 (RNF11), a negative regulator of NF-κB signaling pathway, colocalizes with α-synuclein and is sequestered in Lewy bodies in Parkinson's disease (PD). Since persistent NF-κB activation is reported in PD, in this report we investigated if RNF11 expression level is correlated to activated NF-κB in PD. We examined RNF11 expression levels in correlation to phospho-p65, a marker for activated NF-κB, in control and PD brain tissue from cerebral cortex. In addition we performed double immunofluorescence labeling experiments to confirm this correlation. Our investigations demonstrated that the neuronal RNF11 expression was down-regulated in PD and was usually associated with increased expression of phospho-p65. Double labeling confirmed that loss of neuronal RNF11 was linked to increased phospho-p65 expression, suggesting that persistent presence of NF-κB activation could be due to decreased levels of its negative regulator. Our data exemplifies the relevance of RNF11 and persistent NF-κB activation in PD.
  Neuroscience Letters 05/2013;
• Article: Proton magnetic resonance spectroscopy measures related to short-term symptomatic outcome in chronic schizophrenia.

  Agata Szulc, Beata Konarzewska, Beata Galinska-Skok, Joanna Lazarczyk-Kirejczyk, Napoleon Waszkiewicz, Eugeniusz Tarasow, Robert Milewski, Jerzy Walecki
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  ABSTRACT: INTRODUCTION: Proton magnetic resonance spectroscopy ((1) H MRS) enables the evaluation of in vivo brain function. The purpose of the study was to compare (1)H MRS measurements in schizophrenic patients, who were clinical responders after short-term antipsychotic treatment, with non-responders and healthy controls. METHODS: We investigated a group of 47 patients diagnosed with schizophrenia. Patients were examined twice-once after a period of at least 7 days without neuroleptics and the second time at least 4 weeks after therapy with stable doses of medication. The follow-up was available in 42 patients. Baseline MRS measurements of clinical responders were compared with non-responders and the group of healthy controls (N=26). We assessed the following metabolite ratios: NAA (N-acetylaspartate), Glx (complex of GABA, glutamine and glutamate), Cho (choline) and mI (myo-inositol) to creatinine (Cr) in the left frontal and temporal lobes and the thalamus. Results: Responders showed a significantly lower baseline frontal Glx/Cr level than non-responders. Both groups had a significantly lower NAA/Cr ratio in the frontal lobe than the controls, but only non-responders had a significantly lower NAA/Cr ratio in the thalamus. Conclusions: Our results confirm the relationship between the glutamatergic system and pathophysiology of schizophrenia and suggest a significant value of (1)H MRS examination in the assessment of the future treatment effect.
  Neuroscience Letters 05/2013;
• Article: Modulation of cortical activity in response to visually induced postural perturbation: Combined VR and EEG study.

  Semyon M Slobounov, Elizabeth Teel, Karl M Newell
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  ABSTRACT: There is evidence from EEG studies that unexpected perturbations to standing posture induce a differential modulation of cortical activity compared to self-initiated and/or predictable conditions. However, the neural correlates of whole body postural response to visually-induced perturbations on standing posture have not been examined. Here we employ a novel experimental paradigm via combined Virtual Reality (VR) and EEG measures to examine the effects of visually induced perturbations on the dynamics of postural responses. Twelve Penn State student-athletes without prior history of neurologic disorders and/or orthopaedic injuries participated in this study. There were no differences in response/reaction time measures between both spatially and temporally unpredictable and fully predictable conditions (p>.05). However, significantly stronger modulation of frontal-central EEG theta activity was present prior to onset of unpredictable postural perturbations (p<. 05). It is postulated that enhanced EEG theta in unpredictable conditions reflects increased effort to recruit additional brain resources to meet the demands of the postural tasks.
  Neuroscience Letters 05/2013;
• Article: SUMO-1 conjugation blocks beta-amyloid-induced astrocyte reactivity.

  Juliana B Hoppe, Marcus Rattray, Henry Tu, Christianne G Salbego, Helena Cimarosti
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  ABSTRACT: Astrocyte reactivity is implicated in the neuronal loss underlying Alzheimer's disease. Curcumin has been shown to reduce astrocyte reactivity, though the exact pathways underlying these effects are incompletely understood. Here we investigated the role of the small ubiquitin-like modifier (SUMO) conjugation in mediating this effect of curcumin. In beta-amyloid (Aβ)-treated astrocytes, morphological changes and increased glial fibrillary acidic protein (GFAP) confirmed reactivity, which was accompanied by c-jun N-terminal kinase activation. Moreover, the levels of SUMO-1 conjugated proteins, as well as the conjugating enzyme, Ubc9, were decreased, with concomitant treatment with curcumin preventing these effects. Increasing SUMOylation in astrocytes, by over-expression of constitutively active SUMO-1, but not its inactive mutant, abrogated Aβ-induced increase in GFAP, suggesting astrocytes require SUMO-1 conjugation to remain non-reactive.
  Neuroscience Letters 05/2013;
• Article: Dual Immunofluorescence Study of Citrullinated Proteins in Alzheimer Diseased Frontal Cortex.

  Anthony P Nicholas
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  ABSTRACT: Deimination is a post-translational modification of proteins in which selected arginine amino acids are enzymatically converted to citrullines. Using dual-color immunofluorescence, the present study is the first to examine the frontal cortex of patients with Alzheimer's disease (AD) versus age-matched controls with an established monoclonal antibody (F95) against peptidyl-citrulline moieties. In AD specimens, a number of new findings were discovered, including evidence for deiminated proteins in extracellular plaques, the walls of large blood vessels, the nuclei of selective neurons immunoreactive for phosphorylated tau and numerous reactive astrocytes concentrated around extracellular plaques, ventricular surfaces and at the interface between the gray and white matter of the cortex. Although the identities of these citrullinated proteins remain largely unknown, the present study adds to the growing number of locations in which deiminated proteins may be found in the brains of patients with AD.
  Neuroscience Letters 05/2013;
• Article: Association of P2X7 receptor gene polymorphisms with sporadic Parkinsons disease in a Han Chinese Population.

  Hongxin Liu, Xun Han, Yongsheng Li, Haiqiang Zou, Anmu Xie
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  ABSTRACT: Previous studies have indicated that genetic polymorphisms in the P2X7 receptors may influence the occurrence and development of sporadic Parkinson's diseases (PD). In our study, two DNA polymorphisms at P2X7 receptor gene: 1513 A>C (rs3751143) and 1729T>A (rs1653624) were examined by PCR-RFLP analysis in 285 sporadic patients and 285 healthy controls in Han Chinese Population. For 1513 A>C polymorphism, there were significant differences in genotype distribution in PD group and late-onset PD (LOPD) group relative to the control groups respectively (P=0.015 and P=0.032, respectively),as well as between male PD and the controls subgroup (P=0.031). However, there were no significant differences in the genotype and allele frequencies of 1729T>A polymorphism between groups. Our study revealed that the P2X7 receptors 1513 A>C polymorphism is a risk factor for sporadic PD, LOPD and male PD in Han Chinese population, while 1729T>A polymorphism is not significantly associated with Parkinson's disease.
  Neuroscience Letters 05/2013;
• Article: Spontaneous firing rate changes in cat primary auditory cortex following long-term exposure to non traumatic noise. Tinnitus without hearing loss?

  R Munguia, M Pienkowski, J J Eggermont
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  ABSTRACT: Changes of neural activity in animal models have been correlated with tinnitus in humans. For instance, increased spontaneous firing rates (SFR), increased spontaneous neural synchrony, and cortical tonotopic map reorganization may underlie this phantom auditory percept. The aim of this study is to quantify the changes in SFR activity in the cat primary auditory cortex, after long-term exposure to different types of non-traumatic acoustic environments. For that purpose, four different groups of adult cats were exposed to moderate-level (∼70dB SPL), behaviorally-irrelevant sounds for several weeks to months, and their SFRs were compared with those in control cats. The sounds consisted of random multi-frequency tone pip ensembles with various bandwidths (2-4kHz, 4-20kHz, and a pair of third-octave bands centered at 4 and 16kHz), as well as a "factory noise". Auditory brainstem response (ABR) thresholds, ABR wave 3 amplitudes at ∼55 and 75dB SPL, and distortion product otoacoustic emission (DPOAE) amplitudes were unaffected by the exposure. However, we found that the SFR decreased within the exposure frequency range and increased outside the exposure range. This increased SFR for units with characteristic frequencies outside the exposure frequency range, which was slow to reverse after the exposure offset, suggests a mechanism for tinnitus in the absence of hearing loss.
  Neuroscience Letters 05/2013;
• Article: A novel diterpene para-hydroquinone compound derived from cryptoquinone protects neuronal cells against oxidative stress and activates the Nrf2/ARE pathway.

  Shunsuke Sasaki, Terumasa Tozawa, Kazuhiro Sugamoto, Yoh-Ichi Matsushita, Takumi Satoh
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  ABSTRACT: Green plant-origin electrophilic compounds are a newly-recognized class of neuroprotective compounds that provide neuroprotection through activation of the Nrf2/ARE pathway. Electophilic hydroquinones are of particular interest due to their ability to become electrophilic quinones upon auto-oxidation. Although green plants frequently produce a variety of electrophilic compounds, the detailed mechanisms of action of these compounds remain unknown. Here, we focused on the neuroprotective effects of 11,14-dihydroxy-8,11,13-abietariene (DA1), derived from a para-hydroquinone-type pro-electrophilic compound from the cryptoquinone. DA1 activated the Nrf2/ARE pathway, induced phase 2 enzymes, and increased glutathione, thus protecting neuronal cells from oxidative stress. DA1 had a very broad safety zone (199.41 fold) at least in our system. Thus, DA1 is a novel neuroprotective pro-electrophilic diterpene from green plant.
  Neuroscience Letters 05/2013;
• Article: Lack of association between brain-derived neurotrophic factor Val66Met polymorphism and body mass index change over time in healthy adults.

  Matea Nikolac Perkovic, Maja Mustapic, Mladen Pavlovic, Suzana Uzun, Oliver Kozumplik, Ivan Barisic, Dorotea Muck-Seler, Nela Pivac
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  ABSTRACT: Obesity is becoming the epidemic health problem worldwide with a very complex etiology. The interaction between diverse genetic and environmental factors contributes to development of obesity. Among myriad of functions in central and peripheral tissues, brain-derived neurotrophic factor (BDNF) also regulates energy homeostasis, food intake and feeding behavior, and has a role in obesity and increased body mass index (BMI). BDNF Val66Met (rs6265) polymorphism is associated with BMI gain, but both positive associations and non-replications are reported. Since BMI changes over time and since genetic influences on BMI vary with age, the aim of the study was to evaluate association between BDNF Val66Met polymorphism and BMI gain in healthy subjects with middle or old age. The study included a cohort of 339 adult healthy Caucasians of Croatian origin, free of eating and metabolic disorders, evaluated in three time periods in the year 1972, 1982 and 2006, when the subjects were around 40, 50 and 70 years old, respectively. The results revealed a significant effect of smoking on BMI, but a lack of significant association between BDNF Val66Met polymorphism and overweight or obesity, and no significant association between BDNF Val66Met and BMI changes over time. These results did not confirm the major role of BDNF Val66Met in the regulation of BMI changes in adult and old healthy subjects.
  Neuroscience Letters 05/2013;
• Article: Hippocampal levels of ChAT, PKA, phospho-PKA and phospho-CaMKIIα but not CaMKIIα positively correlate with spatial learning skills in rats.

  Ciğdem Gökçek-Saraç, Orhan Adalı, Ewa Jakubowska-Doğru
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  ABSTRACT: Despite very extensive investigations on molecular processes underlying memory formation, there are very few studies examining potential differences in the brain biochemistry between "good" and "poor" learners belonging to a random population of young animals. In the present study, an attempt was made to correlate individual variation in spatial learning in young-adult Long-Evans rats with hippocampal levels of protein kinase A (PKA), calcium/calmodulin-dependent protein kinase II alpha (CaMKIIα), and choline acetyltransferase (ChAT). Additionally, in order to indirectly estimate the activity of CaMKIIα and PKA, hippocampal levels of their phosphorylated forms (pCaMKIIα and pPKA) were assessed using Western Blot technique. Rats were classified as "good" and "poor" learners on the basis of their performance in a partially baited 12-arm radial maze. The biochemical assays did not reveal a significant difference in the basal hippocampal levels of the CaMKIIα, however, the level of pCaMKIIα, was significantly higher in "good" learners. Also, hippocampal levels of both PKA and pPKA, as well as that of ChAT, were significantly higher in "good" as compared to "poor" learners. Our results suggest that the differences in the expression level of PKA and ChAT (but not of CaMKIIα), as well as the differences in the activation of both PKA and CaMKIIα, may contribute to the individual variation in learning skills and episodic-like memory in a random population of young-adult subjects.
  Neuroscience Letters 05/2013;
• Article: Does increasing the ratio of AMPA-to-NMDA receptor mediated neurotransmission engender antidepressant action? Studies in the mouse forced swim and tail suspension tests.

  Jesper T Andreasen, Mikko Gynther, Allan Rygaard, Trine Bøgelund, Simon D Nielsen, Rasmus P Clausen, Jesper Mogensen, Darryl S Pickering
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  ABSTRACT: Monoamine-based antidepressant drugs increase α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) function and decrease N-Methyl-D-aspartate receptor (NMDAR) function. The NMDAR antagonist ketamine shows potent antidepressant action in humans and the antidepressant-like effects of ketamine and monoamine-based antidepressants in rodents depend on increased AMPAR throughput. Further, the antidepressant-like effects of monoamine-based antidepressants are enhanced by AMPAR potentiation and by NMDAR antagonism. This has led to a hypothesis that antidepressant efficacy involves an increases ratio of AMPAR-to-NMDAR-mediated neurotransmission. To further elucidate the interaction of AMPAR, NMDAR and monoamine transmission we tested combinations of the AMPAR positive allosteric modulator (AMPA potentiator), (R,R)-N,N-(2,20-[biphenyl-4-40-diyl]bis[propane-2,1-diyl])dimethanesulfonamide (PIMSD), with: the uncompetitive NMDAR antagonist MK-801; nicotine, which has potent glutamate-releasing properties; and the selective serotonin reuptake inhibitor escitalopram using the mouse forced swim (mFST) and tail suspension tests (mTST). MK-801, nicotine or escitalopram did not induce antidepressant-like effects in either of the two tests. PIMSD enhanced the effect of MK-801 in the mFST, supporting the hypothesis that increasing AMPAR-to-NMDAR-mediated neurotransmission conveys antidepressant action. Nicotine-induced glutamate release simultaneously activates NMDARs and AMPARs and showed no net effect in the mFST when given alone. However, increasing the ratio of AMPAR-to-NMDA-R transmission by favouring AMPAR throughput with PIMSD revealed an antidepressant-like action of nicotine in the mFST. PIMSD also enhanced the effect of escitalopram treatment in the mFST and mTST, supporting existing evidence and suggesting a synergistic effect of simultaneously facilitating monoamine transmission and increasing the ratio of AMPAR-to-NMDAR throughput. No synergistic effects of the PIMSD+MK-801 or PIMSD+nicotine were found in the mTST, indicating a differential sensitivity of mFST and mTST when investigating glutamate-based antidepressant mechanisms. This study corroborates existing evidence that there may be an unexploited therapeutic potential in treating depression by directly increasing the ratio of AMPAR-to-NMDAR neurotransmission, possibly in combination with monoamine-based mechanisms.
  Neuroscience Letters 05/2013;