Experimental Neurology (EXP NEUROL)

Publications in this journal

• Article: Dopaminergic Modulation of Tonic but not Phasic GABAA Current in the Ventrobasal Thalamus of Wistar and GAERS rats

  Josue G. Yagüe, Anna Cavaccini Cavaccini, Adam C. Errington, Vincenzo Crunelli, Giuseppe Di Giovanni
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  ABSTRACT: Activation of GABAA receptors by GABA causes phasic and tonic conductances in different brain areas. In the ventrobasal (VB) thalamus, tonic inhibition originates from GABA acting on extrasynaptic receptors. Here we show that dopamine (DA), the D2-like agonist quinpirole and the selective D4R agonist PD-168,077 decrease the magnitude of the tonic GABAA current whilst D1-like agonist SKF39383 lacks any significant effects in VB neurons of Wistar rats. On the other hand, DA and D1/D2 receptor activation does not alter phasic GABAA conductance. As we previously reported that an increased tonic GABAA current in VB neurons is critical for absence seizure generation, we also investigated whether D2-D4 receptor activation is capable of normalizing this aberrant conductance in Genetic Absence Epilepsy Rats from Strasbourg (GAERS). Quinpirole and PD-168,077 selectively reduces tonic GABAA current as in normal rats. Therefore, it is conceivable that some DA anti-absence effects occur via modulation of tonic GABAA current in the VB.
  Experimental Neurology 03/2013; in press.
• Article: Attenuation of MPTP neurotoxicity by rolipram, a specific inhibitor of phosphodiesterase IV.

  Lichuan Yang, Noel Y Calingasan, Beverly J Lorenzo, M Flint Beal
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  ABSTRACT: Rolipram, a specific inhibitor of the phosphodiesterase IV (PDE IV), has recently been shown to exert neuroprotective effects in an Alzheimer transgenic mouse model and in hypoxic-ischemic damage in the rat brain. It activates the cAMP-dependent protein kinase (PKA)/cAMP regulatory element-binding protein (CREB) signaling pathway and it inhibits inflammation. We tested the neuroprotective effects of the specific PDE IV inhibitor rolipram in C57BL/6 mice treated with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). We found that rolipram administered at 1.25 mg/kg or 2.5 mg/kg doses significantly attenuated MPTP-induced dopamine depletion in the striatum, and reduced the loss of tyrosine hydroxylase-positive neurons in the substantia nigra. There was a bell-shaped dose effect with greater efficacy at the 1.25 mg/kg dose than 2.5 mg/kg and a higher dose of rolipram, 5 mg/kg, had no protective effect and even increased the mortality of animals when co-administered with MPTP. Rolipram did not interact with MPTP in its absorption into the brain and in its metabolism to 1-methyl-4-phenylpyridinium (MPP(+)). Our data show a neuroprotective effect of the PDE IV specific inhibitor rolipram against dopaminergic neuron degeneration, suggesting that PDE IV inhibitors might be a potential treatment for Parkinson's disease.
  Experimental Neurology 06/2008; 211(1):311-4.
• Article: Mitochondrial fusion and function in Charcot-Marie-Tooth type 2A patient fibroblasts with mitofusin 2 mutations.

  Elizabeth A Amiott, Paul Lott, Jamie Soto, Peter B Kang, J Michael McCaffery, Salvatore DiMauro, E Dale Abel, Kevin M Flanigan, Victoria H Lawson, Janet M Shaw
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  ABSTRACT: Charcot-Marie-Tooth Type 2A is a dominantly inherited peripheral neuropathy characterized by axonal degeneration of sensory and motor nerves. The disease is caused by mutations in the mitochondrial fusion gene MFN2. Mfn2 is an integral outer mitochondrial membrane protein composed of a large GTPase domain and two heptad repeat (HR) domains that face the cytoplasm. Mitochondrial membrane fusion and division are balanced processes that are necessary to maintain tubular mitochondrial morphology, respiratory function, and uniform distribution of the organelle throughout the cell. We have utilized primary fibroblasts from CMT2A patients to survey mitochondrial phenotypes associated with heterozygous MFN2 alleles expressed at physiological levels. Our results indicate that, in fibroblasts, mitofusin expression, mitochondrial morphology, ultrastructure, mtDNA content, and respiratory capacity are not affected by the presence of mutant Mfn2 protein. Consistent with a lack of mitochondrial dysfunction, we also show that mitochondrial fusion occurs efficiently in CMT2A patient-derived fibroblasts. Our observations are in agreement with the neuronal specificity of the disease and are consistent with a recent finding that mitochondrial fusion can be maintained in cells that express mutant Mfn2 protein due to complementation by a second mitofusin, Mfn1. We discuss our results and those of others in terms of a comprehensive model for the mechanism(s) by which mutations in MFN2 may lead to CMT2A disease.
  Experimental Neurology 06/2008; 211(1):115-27.
• Article: Novel computational models for predicting dopamine interactions.

  Alan R Katritzky, Dimitar A Dobchev, Iva B Stoyanova-Slavova, Minati Kuanar, Maxim M Bespalov, Mati Karelson, Mart Saarma
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  ABSTRACT: Dopamine is a crucial neurotransmitter responsible for functioning and maintenance of the nervous system. Dopamine has also been implicated in a number of diseases including schizophrenia, Parkinson's disease and drug addiction. Dopamine agonists are used in early Parkinson's disease treatment. Dopamine antagonists suppress schizophrenia. Therefore, molecules modulating dopamine receptors activity are vastly important for understanding the nervous system functioning and for the treatment of neurological diseases. In this study we describe novel computational models that efficiently predict binding affinity of the existing small molecule dopamine analogs to dopamine receptor. The model provides the set of molecular descriptors that can be used for the development of new small molecule dopamine agonists.
  Experimental Neurology 06/2008; 211(1):150-71.
• Article: The role of AMPA receptor modulation in the treatment of neuropsychiatric diseases.

  Carlos A Zarate, Husseini K Manji
  Experimental Neurology 06/2008; 211(1):7-10.
• Article: Ketogenic diet: stoking energy stores and still posing questions.

  Ina Knerr, Phillip L Pearl
  Experimental Neurology 06/2008; 211(1):11-3.
• Article: Mice lacking the transcription factor Ikaros display behavioral alterations of an anti-depressive phenotype.

  Tim-Rasmus Kiehl, Sandra E Fischer, Shereen Ezzat, Sylvia L Asa
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  ABSTRACT: The Ikaros (Ik) family of transcription factors has critical functions in immune regulation, lymphohematopoiesis and the hypothalamic-pituitary axis. Ik influences cell fate decisions through transcriptional activation of target genes and its interaction with chromatin remodeling complexes. While Ik is well-described in the lymphoid system and pituitary, its presence and function in the brain has received limited attention to date. This study describes the transient spatio-temporal expression of Ik in striatal medium spiny neurons of the developing murine CNS. To determine the impact of Ik deficiency, standardized behavioral tests were performed. In the elevated plus-maze and contextual fear conditioning tests, homozygous Ik-deficient mice performed similarly to wild-type or heterozygote mice. However, significant differences were observed in Ik-null mice in several behavioral tests. Pinch-induced catalepsy was markedly extended. In the Porsolt forced swim test, Ik-null mice showed reduced immobility, consistent with an anti-depressive effect. The acoustic startle response of Ik-null mice was also markedly diminished. Our findings extend the role of the Ikaros zinc-finger protein to the maturation and differentiation of striatal medium spiny neurons and indicate important actions for Ik in the development of neurocognitive functions and affecting depressive behaviors.
  Experimental Neurology 06/2008; 211(1):107-14.
• Article: The systemic inflammatory response after spinal cord injury damages lungs and kidneys.

  Denis Gris, Eilis F Hamilton, Lynne C Weaver
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  ABSTRACT: Spinal cord injury (SCI) triggers a well characterized, acute, local inflammation leading to secondary damage at the lesion site. Another little recognized problem may be the activation of circulating inflammatory cells that potentially damage tissues outside the cord. We investigated this problem using severe clip-compression SCI in rats. We studied systemic inflammation after SCI and its effects on lungs and kidneys, as dysfunction of these organs is a frequent, early complication after SCI. From 2-24 h after SCI, the number of circulating neutrophils (especially immature cells) significantly increased by 3-10 fold. Flow cytometry experiments revealed that SCI transiently activates these neutrophils, causing increased oxidative responses to phorbolmyristic acid at 2 h after SCI; then, from 4-24 h, the neutrophils were less responsive. Neutrophil longevity was increased (30-50% decrease in apoptosis) at 2-8 h after SCI. Immunohistochemical analyses demonstrated the invasion of neutrophils into lungs and kidneys (2 h-7 d after SCI) and more phagocytic macrophages in lungs (12 h, 3 d after SCI). Myeloperoxidase and matrix metalloproteinase-9 activity in lung and kidney homogenates increased (12 h-7 d after SCI). Expression of COX-2 increased and lipid peroxidation also occurred within this time. Control experiments inducing local cord damage by excitotoxic quisqualate injection verified that SCI per se is sufficient to trigger systemic inflammation and organ damage. In summary, SCI mobilizes and activates neutrophils that then migrate into visceral organs, a phenomenon occurring in parallel with their well-known entry into the cord injury site. The systemic inflammatory response to SCI should be targeted in the development of new therapeutic strategies to treat SCI.
  Experimental Neurology 06/2008; 211(1):259-70.
• Article: Manually-stimulated recovery of motor function after facial nerve injury requires intact sensory input.

  Stoyan P Pavlov, Maria Grosheva, Michael Streppel, Orlando Guntinas-Lichius, Andrey Irintchev, Emmanouil Skouras, Srebrina K Angelova, Stefanie Kuerten, Nektarios Sinis, Sarah A Dunlop, Doychin N Angelov
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  ABSTRACT: We have recently shown in rat that daily manual stimulation (MS) of vibrissal muscles promotes recovery of whisking and reduces polyinnervation of muscle fibers following repair of the facial nerve (facial-facial anastomosis, FFA). Here, we examined whether these positive effects were: (1) correlated with alterations of the afferent connections of regenerated facial motoneurons, and (2) whether they were achieved by enhanced sensory input through the intact trigeminal nerve. First, we quantified the extent of total synaptic input to motoneurons in the facial nucleus using synaptophysin immunocytochemistry following FFA with and without subsequent MS. We found that, without MS, this input was reduced compared to intact animals. The number of synaptophysin-positive terminals returned to normal values following MS. Thus, MS appears to counteract the deafferentation of regenerated facial motoneurons. Second, we performed FFA and, in addition, eliminated the trigeminal sensory input to facial motoneurons by extirpation of the ipsilateral infraorbital nerve (IONex). In this paradigm, without MS, vibrissal motor performance and pattern of end-plate reinnervation were as aberrant as after FFA without MS. MS did not influence the reinnervation pattern after IONex and functional recovery was even worse than after IONex without MS. Thus, when the sensory system is intact, MS restores normal vibrissal function and reduces the degree of polyinnervation. When afferent inputs are abolished, these effects are eliminated or even reversed. We conclude that rehabilitation strategies must be carefully designed to take into account the extent of motor and/or sensory damage.
  Experimental Neurology 06/2008; 211(1):292-300.
• Article: Deficits in social behavior and reversal learning are more prevalent in male offspring of VIP deficient female mice.

  Conor M Stack, Maria A Lim, Katrina Cuasay, Madeleine M Stone, Kimberly M Seibert, Irit Spivak-Pohis, Jacqueline N Crawley, James A Waschek, Joanna M Hill
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  ABSTRACT: Blockage of vasoactive intestinal peptide (VIP) receptors during early embryogenesis in the mouse has been shown to result in developmental delays in neonates, and social behavior deficits selectively in adult male offspring. Offspring of VIP deficient mothers (VIP +/-) also exhibited developmental delays, and reductions in maternal affiliation and play behavior. In the current study, comparisons among the offspring of VIP deficient mothers (VIP +/-) mated to VIP +/- males with the offspring of wild type (WT) mothers mated to VIP +/- males allowed assessment of the contributions of both maternal and offspring VIP genotype to general health measures, social behavior, fear conditioning, and spatial learning and memory in the water maze. These comparisons revealed few differences in general health among offspring of WT and VIP deficient mothers, and all offspring exhibited normal responses in fear conditioning and in the acquisition phase of spatial discrimination in the water maze. WT mothers produced offspring that were normal in all tests; the reduced VIP in their VIP +/- offspring apparently did not contribute to any defects in the measures under study. However, regardless of their own VIP genotype, all male offspring of VIP deficient mothers exhibited severe deficits in social approach behavior and reversal learning. The deficits in these behaviors in the female offspring of VIP deficient mothers were less severe than in their male littermates, and the extent of their impairment was related to their own VIP genotype. This study has shown that intrauterine conditions had a greater influence on behavioral outcome than did genetic inheritance. In addition, the greater prevalence of deficits in social behavior and the resistance to change seen in reversal learning in the male offspring of VIP deficient mothers indicate a potential usefulness of the VIP knockout mouse in furthering the understanding of neurodevelopmental disorders such as autism.
  Experimental Neurology 06/2008; 211(1):67-84.
• Article: Continuous delivery of ropinirole reverses motor deficits without dyskinesia induction in MPTP-treated common marmosets.

  K A Stockwell, D J Virley, M Perren, M M Iravani, M J Jackson, S Rose, P Jenner
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  ABSTRACT: L-DOPA treatment of Parkinson's disease induces a high incidence of motor complications, notably dyskinesia. Longer acting dopamine agonists, e.g. ropinirole, are thought to produce more continuous dopaminergic stimulation and less severe dyskinesia. However, standard oral administration of dopamine agonists does not result in constant plasma drug levels, therefore, more continuous drug delivery may result in both prolonged reversal of motor deficits and reduced levels of dyskinesia. Therefore, we compared the effects of repeated oral administration of ropinirole to constant subcutaneous infusion in MPTP-treated common marmosets. Animals received oral administration (0.4 mg/kg, BID) or continuous infusion of ropinirole (0.8 mg/kg/day) via osmotic minipumps for 14 days (Phase I). The treatments were then switched and continued for a further 14 days (Phase II). In Phase I, locomotor activity was similar between treatment groups but reversal of motor disability was more pronounced in animals receiving continuous infusion. Dyskinesia intensity was low in both groups however there was a trend suggestive of less marked dyskinesia in those animals receiving continuous infusion. In Phase II, increased locomotor activity was maintained but animals switched from oral to continuous treatment showing an initial period of enhanced locomotor activity. The reversal of motor disability was maintained in both groups, however, motor disability tended towards greater improvement following continuous infusion. Importantly, dyskinesia remained low in both groups suggesting that constant delivery of ropinirole neither leads to priming nor expression of dyskinesia. These results suggest that a once-daily controlled-release formulation may provide improvements over existing benefits with standard oral ropinirole in Parkinson's disease patients.
  Experimental Neurology 06/2008; 211(1):172-9.
• Article: Immediate electrical stimulation enhances regeneration and reinnervation and modulates spinal plastic changes after sciatic nerve injury and repair.

  Meritxell Vivó, Antoni Puigdemasa, Laura Casals, Elena Asensio, Esther Udina, Xavier Navarro
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  ABSTRACT: We have studied whether electrical stimulation immediately after nerve injury may enhance axonal regeneration and modulate plastic changes at the spinal cord level underlying the appearance of hyperreflexia. Two groups of adult rats were subjected to sciatic nerve section followed by suture repair. One group (ES) received electrical stimulation (3 V, 0.1 ms at 20 Hz) for 1 h after injury. A second group served as control (C). Nerve conduction, H reflex, motor evoked potentials, and algesimetry tests were performed at 1, 3, 5, 7 and 9 weeks after surgery, to assess muscle reinnervation and changes in excitability of spinal cord circuitry. The electrophysiological results showed higher levels of reinnervation, and histological results a significantly higher number of regenerated myelinated fibers in the distal tibial nerve in group ES in comparison with group C. The monosynaptic H reflex was facilitated in the injured limb, to a higher degree in group C than in group ES. The amplitudes of motor evoked potentials were similar in both groups, although the MEP/M ratio was increased in group C compared to group ES, indicating mild central motor hyperexcitability. Immunohistochemical labeling of sensory afferents in the spinal cord dorsal horn showed prevention of the reduction in expression of substance P at one month postlesion in group ES. In conclusion, brief electrical stimulation applied after sciatic nerve injury promotes axonal regeneration over a long distance and reduces facilitation of spinal motor responses.
  Experimental Neurology 06/2008; 211(1):180-93.
• Article: Pallidal burst activity during therapeutic deep brain stimulation.

  Philip J Hahn, Gary S Russo, Taka Hashimoto, Svjetlana Miocinovic, Weidong Xu, Cameron C McIntyre, Jerrold L Vitek
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  ABSTRACT: Theoretical and experimental analyses of deep brain stimulation (DBS) in the subthalamic nucleus (STN) show both excitatory and inhibitory effects on the neural elements surrounding the electrode. Given these observations, the mechanism underlying the therapeutic effect of STN DBS on parkinsonian motor signs remains under debate. One hypothesis suggests that abnormal levels of bursting activity in the pallidum play a key role in the development of parkinsonian motor signs and that STN DBS may exert its beneficial effect by modifying this type of activity. We quantified the changes in bursting activity of globus pallidus internus (GPi) and externus (GPe) neurons before and during ineffective (subtherapeutic) and effective (therapeutic) STN DBS in two monkeys rendered parkinsonian by the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Compared to pre-stimulation control values, the population mean firing rate increased during therapeutic stimulation significantly in both GPe (from 41.7 Hz+/-2.8 to 71.4 Hz+/-7.8) and GPi (from 58.8 Hz+/-4.2 to 71.5 Hz+/-6.2). The burst rate, however, increased significantly in GPe (from 80.1 bursts/min+/-10.0 to 103.1 bursts/min+/-11.1) and decreased significantly in GPi (from 104.2 bursts/min+/-8.3 to 75.8 bursts/min+/-10.8). Although both animals showed improvement in parkinsonian motor signs, changes in rate and bursting activity in GPi were significant only in one animal. These data suggest that while changes in rate and bursting activity may contribute to the improvement in PD motor signs during STN DBS, one cannot explain the therapeutic effects of stimulation in all cases solely on changes in these parameters. Other physiological changes that contribute to its therapeutic effect must also occur.
  Experimental Neurology 06/2008; 211(1):243-51.
• Article: Crosstalk between astrocytes and motor neurons: what is the message?

  L Van Den Bosch, W Robberecht
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  ABSTRACT: Motor neuron death as seen in amyotrophic lateral sclerosis (ALS) is likely to be a non-cell autonomous process. One cell type that may be involved in the pathogenesis of the disease is the astrocyte. Under normal conditions, astrocytes affect survival of motor neurons by releasing growth factors and removing glutamate from the synaptic cleft. In addition, they determine some of the functional characteristics of motor neurons. In turn, motor neurons affect the functional characteristics of astrocytes. Recent evidence suggests that activation of astrocytes in a degenerative disease like ALS leads to a disturbance of this crosstalk between astrocytes and motor neurons, and that this may contribute to the death of motor neurons. As a consequence, understanding the interactions between motor neurons and astrocytes in health and disease may have important therapeutic implications.
  Experimental Neurology 06/2008; 211(1):1-6.
• Article: Combined treatment with atorvastatin and minocycline suppresses severity of EAE.

  Ilaria Luccarini, Clara Ballerini, Tiziana Biagioli, Filippo Biamonte, Arianna Bellucci, Maria Cristina Rosi, Cristina Grossi, Luca Massacesi, Fiorella Casamenti
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  ABSTRACT: Multiple sclerosis (MS) is the most common inflammatory demyelinating disorder of the central nervous system (CNS). An approach to improve MS treatment is to identify a rational combination of new medications or existing therapies that impact different aspects of the disease process. Statins are effective in the treatment of MS animal models and are promising candidates for future treatment. Minocycline ameliorates clinical severity of experimental autoimmune encephalomyelitis (EAE) and exhibits several anti-inflammatory and neuroprotective activities. In this study, we tested whether the combination of these two drugs could produce beneficial effects in EAE mice immunized with myelin oligodendrocyte protein (MOG). Our findings show that combined treatment, compared to using the medications alone, resulted in a significant reduction in disease severity, in both the acute and chronic phases of the disease, along with attenuation of inflammation, demyelination and axonal loss. Stereological analysis revealed that the combined treatment significantly guarded against neuroinflammation and neurodegeneration. Moreover, a significant suppression of anti-MOG antibody production in animals treated with the two medications was found. In conclusion, our findings prove that this combination of drugs is neuroprotective and suppresses the severity of EAE. Furthermore, this pharmacological approach appears to be promising as a future therapeutic strategy to control MS.
  Experimental Neurology 06/2008; 211(1):214-26.