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PubMed2003

Sox1-deficient mice suffer from epilepsy associated with abnormal ventral forebrain development and olfactory cortex hyperexcitability.

Mutations in several classes of embryonically-expressed transcription factor genes are associated with behavioral disorders and epilepsies. However, there is little known about how such genetic and neurodevelopmental defects lead to brain dysfunction. Here we present the characterization of an epilepsy syndrome caused by the absence of the transcription factor SOX1 in mice. In vivo electroencephalographic recordings from SOX1 mutants established a correlation between behavioral changes and cortical output that was consistent with a seizure origin in the limbic forebrain. In vitro intracellular recordings from three major forebrain regions, neocortex, hippocampus and olfactory (piriform) cortex (OC) showed that only the OC exhibits abnormal enhanced synaptic excitability and spontaneous epileptiform discharges. Furthermore, the hyperexcitability of the OC neurons was present in mutants prior to the onset of seizures but was completely absent from both the hippocampus and neocortex of the same animals. The local inhibitory GABAergic neurotransmission remained normal in the OC of SOX1-deficient brains, but there was a severe developmental deficit of OC postsynaptic target neurons, mainly GABAergic projection neurons within the olfactory tubercle and the nucleus accumbens shell. Our data show that SOX1 is essential for ventral telencephalic development and suggest that the neurodevelopmental defect disrupts local neuronal circuits leading to epilepsy in the SOX1-deficient mice.

Animals↗

PubMed1998

Future developments.

Neuronal signalling cannot always be reduced to classical synaptic transmission resulting in a binary inhibition or excitation. Many types of molecules that are bioactive do not fit readily into the profile of a classical neurotransmitter. Release of bioactive substances can occur beyond the familiar axonal synapse. The actions of bioactive substances, including classical transmitters, can be modulatory, global and long term. It is erroneous to extrapolate from events at the level of the neuron or gene to wholescale functions and dysfunctions. The actions of bioactive substances have to be appreciated within the context of neuronal populations, and in turn within the holistic anatomical context of the brain. Molecular biology will contribute to this more precise understanding of the relationship between individual genes, gene mutations, molecular and cellular phenotypes, and corresponding functions and dysfunctions.

Animals↗

PubMed2004

Impaired GABA neuronal response to acute benzodiazepine administration in panic disorder.

OBJECTIVE: Disturbances in the metabolism of the brain amino acid transmitter gamma-aminobutyric acid (GABA) may contribute to the pathophysiology of human anxiety disorders. Animal studies indicate that deletions or reductions in the expression of the gene for the GABA synthetic enzyme, glutamate decarboxylase 65 (GAD(65)), reduce basal cortical GABA levels or stress-induced release of GABA in the cerebral cortex and increase fear behaviors. Complementing these findings, the authors recently observed lower than normal cortical GABA levels in patients with panic disorder. In the current study, the authors tested the hypothesis that panic disorder patients have a deficient GABA neuronal response to benzodiazepine (clonazepam) administration. METHOD: In a parallel-group, repeated-measures design, occipital cortex GABA responses to acute oral, open-label benzodiazepine administration were tested in 10 panic disorder patients and nine healthy comparison subjects. Occipital cortex total GABA levels were measured before and after medication administration by means of a novel proton magnetic resonance spectroscopic technique. RESULTS: Panic disorder patients had a deficient GABA neuronal response (blunted reduction of occipital cortex GABA level) to acute benzodiazepine administration, compared to the healthy subjects, who exhibited a significant decrease in occipital cortex GABA levels after this intervention. The patients also appeared to have persistently low occipital cortex GABA after chronic benzodiazepine treatment. CONCLUSIONS: Overall, these data are consistent with the hypothesis that a trait-like abnormality in GABA neuronal function contributes to the pathogenesis of human panic disorder. The data raise the possibility that GAD(65) enzyme dysfunction could be a pathogenic factor in panic disorder.

Adult↗

PubMed1999

Treatment with AC pulsed electromagnetic fields improves olfactory function in Parkinson's disease.

Olfactory dysfunction is a common symptom of Parkinson's disease (PD). It may manifest in the early stages of the disease and infrequently may even antedate the onset of motor symptoms. The cause of olfactory dysfunction in PD remains unknown. Pathological changes characteristic of PD (i.e., Lewy bodies) have been demonstrated in the olfactory bulb which contains a large population of dopaminergic neurons involved in olfactory information processing. Since dopaminergic drugs do not affect olfactory threshold in PD patients, it has been suggested that olfactory dysfunction in these patients is not dependent on dopamine deficiency. I present two fully medicated Parkinsonian patients with long standing history of olfactory dysfunction in whom recovery of smell occurred during therapeutic transcranial application of AC pulsed electromagnetic fields (EMFs) in the picotesla flux density. In both patients improvement of smell during administration of EMFs occurred in conjunction with recurrent episodes of yawning. The temporal association between recovery of smell and yawning behavior is remarkable since yawning is mediated by activation of a subpopulation of striatal and limbic postsynaptic dopamine D2 receptors induced by increased synaptic dopamine release. A high density of dopamine D2 receptors is present in the olfactory bulb and tract. Degeneration of olfactory dopaminergic neurons may lead to upregulation (i.e., supersensitivity) of postsynaptic dopamine D2 receptors. Presumably, small amounts of dopamine released into the synapses of the olfactory bulb during magnetic stimulation may cause activation of these supersensitive receptors resulting in enhanced sense of smell. Interestingly, in both patients enhancement of smell perception occurred only during administration of EMFs of 7 Hz frequency implying that the release of dopamine and activation of dopamine D2 receptors in the olfactory bulb was partly frequency dependent. In fact, weak magnetic fields have been found to cause interaction with biological systems only within narrow frequency ranges (i.e., frequency windows) and the existence of such frequency ranges has been explained on the basis of the cyclotron resonance model.

Aged↗

PubMed1983

The pathogenesis of neuropsychiatric lupus.

Neuropsychiatric lupus is a frequent and serious complication of systemic lupus erythematosus. Although its pathogenesis has not been fully elucidated several mechanisms based on findings in animals and humans have been proposed: cerebral vasculitis; the cross-reaction of lymphocytotoxic antibodies with brain tissue; choroid plexus dysfunction; and the blocking of neurotransmission by noncytotoxic antibodies. Any or all of these mechanisms may be active in a particular patient at a given time.

Brain↗

PubMed2002

Mice overexpressing CRH show reduced responsiveness in plasma corticosterone after a5-HT1A receptor challenge.

Corticotropin-releasing hormone (CRH) overproduction and serotonergic dysfunction have both been implicated in a range of psychiatric disorders, such as anxiety and depression, and several studies have shown interactions between these two neurotransmitter systems. In this study, we investigated the effects of CRH challenge on hypothalamo-pituitary-adrenal (HPA) axis activity in female transgenic mice overproducing CRH. Furthermore, the effects of mild stress on HPA axis activity and body temperature were investigated in these mice. Pre- and post-synaptic 5-HT1A receptor function were studied by monitoring body temperature and plasma corticosterone levels after challenge with the 5-HT1A receptor agonist 8-hydroxy-2-(di-n-propyl-amino)-tetralin (8-OH-DPAT). Hypothermia in response to 8-OH-DPAT treatment did not differ between transgenic and wild type mice, indicating unaltered somatodendritic 5-HT1A autoreceptor function in mice overproducing CRH. In wild type mice 8-OH-DPAT increased plasma corticosterone levels, but not in transgenic animals. CRH injection, however, increased corticosterone levels in both groups. These data suggest desensitization of post-synaptic, but not pre-synaptic, 5-HT1A receptors in mice overproducing CRH. These findings resemble those seen in depressed patients following 5-HT1A challenge, which is in accord with the hypothesized role of CRH in the pathogenesis of depression.

8-Hydroxy-2-(di-n-propylamino)tetralin↗

PubMed2000

Amyloid beta-peptide effects on synaptosomes from apolipoprotein E-deficient mice.

Apolipoprotein E (apoE) is present in the brain and may contribute to neurophysiologic or neuropathologic events, depending on environmental and genetic influences. Recent studies indicate a role for apoE in synaptic plasticity and maintenance of synaptic membrane symmetry, suggesting that apoE may be involved in regulating synaptic homeostasis. In the present study, cerebrocortical synaptosomes were prepared from transgenic mice lacking apoE (apoE KO) to analyze the possible contribution of apoE toward maintaining homeostasis in synaptosomes. Synaptosomal preparations from apoE KO and wild-type mice exhibited similar basal levels of reactive oxygen species, mitochondrial function, and caspase activity; however, following application of amyloid beta-peptide [Abeta(1-40)], apoE KO synaptosomes displayed increased levels of oxidative stress, mitochondrial dysfunction, and caspase activation compared with synaptosomes from wild-type mice. Synaptosomal membranes from apoE KO mice were more fluid than wild-type synaptosomes and contained higher levels of thiobarbituric acid-reactive substances, consistent with elevated levels of lipid peroxidation occurring in the synapses of apoE KO mice. Together, these data are consistent with a role for apoE in maintaining homeostasis by attenuating oxidative stress, caspase activation, and mitochondrial homeostasis in synapses.

Amyloid beta-Peptides↗

PubMed1985

Autonomic dysfunction in experimental allergic neuritis.

Beat-to-beat variation (R-R variation) in the electrocardiogram was studied in experimental allergic neuritis in the Sprague-Dawley rat. Reduced R-R variations were found in 2 of 10 animals, probably as a sign of autonomic dysfunction. The vagal nerves from these two animals, studied in vitro, showed disturbed conduction. In one animal prolonged conduction latencies to supramaximal electrical stimuli were found. Vagal nerves from controls and from animals without clinical symptoms showed normal conduction. Histologically, the vagal nerves from affected animals showed a slight inflammatory cell infiltration and signs of demyelination but there was no evidence of involvement of the brainstem vasomotor nuclei. Thus, we suggest that the autonomic dysfunction in experimental allergic neuritis, measured as reduced R-R variations, is caused by a peripheral vagal neuropathy.

Animals↗

PubMed1992

Acute polyneuropathy due to lightning injury.

The case of a 19 year old man struck by lightning is described. He sustained quadriplegia for several months and fully recovered. It is suggested that his weakness was due to extensive peripheral nerve damage. In addition, he displayed many well recognised medical complications of lightning injury including acute renal failure, rhabdomyolysis, respiratory distress syndrome, autonomic dysfunction, perforated ear drum, uveitis and cataract. The literature relating to the neurology of lightning strike is briefly reviewed.

Acute Disease↗

PubMed2002

[Genetic hypothesis of schizophrenia].

It is now well demonstrated from family, adoption or twin studies, that genetic factors are involved in schizophrenia. Yet, the nature of these factors remains unknown. The disappointing results of the classical linkage studies are explained by the complex non mendelian inheritance, involving several genes interacting with environmental and/or maturation processes, and the heterogeneity of the clinical expression. The identification of genes having an influence on schizophrenia requires thus new strategies including statistical analysis with no assumption on the inheritance mode (non parametric methods) and the dissection of the heterogeneous syndrome using endophenotypes and/or relevant clinical features. Beside the hypothesis of a dysfunctional neurotransmission in schizophrenia (i.e. dopaminergic), evidence suggests that genes involved in neurodevelopment could also be candidate. The observation of caryotypic anomalies could also lead to new candidate regions or genes.

Brain↗

PubMed2002

Survival signaling and selective neuroprotection through glutamatergic transmission.

In the brain, alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) receptors mediate glutamatergic neurotransmission and, when intensely activated, can induce excitotoxic cell death. In addition to their ionotropic properties, however, AMPA receptors have been functionally coupled to a variety of signal transduction events involving Src-family kinases, G-proteins, and the mitogen-activated protein kinase (MAPK). In the present study, we tested whether AMPA receptors are linked to appropriate signaling events in order to prevent neuronal injury and/or enhance recovery. AMPA stimulation in hippocampal slice cultures caused the selective activation of MAPK through the upstream activator MAPK kinase (MEK). Inhibition of either component of the AMPA receptor--MAPK pathway potentiated cellular damage due to serum deprivation, suggesting that this pathway facilitates compensatory signals in response to injury. Correspondingly, positive modulation of AMPA receptors with the Ampakine 1-(quinoxalin-6-ylcarbonyl)piperidine (CX516) enhanced MAPK activation and reduced the extent of synaptic and neuronal degeneration resulting from excitotoxic episodes. CX516 was neuroprotective when infused into slices either before or after the insult. The Ampakine derivative also elicited neuroprotection in an in vivo model of excitotoxicity as evidenced by reduction in lesion size and preservation of two different types of neurons. Interestingly, the AMPA receptor--MAPK pathway selectively protects against excitotoxicity since enhancing the pathway did not protect against the nonexcitotoxic, slow pathology initiated by lysosomal dysfunction. The results indicate that glutamatergic communication is important for cellular maintenance and that AMPA receptors activate survival signals to counterpoise their own excitotoxic potential.

Allosteric Regulation↗

PubMed2005

Cannabinoids in anaesthesia and pain therapy.

PURPOSE OF REVIEW: Cannabinoids have been known for their analgesic, anxiolytic, antiemetic and antispastic properties for many centuries. Since an endogenous cannabinoid system has been identified in the past two decades, cannabinoids have also become the focus of interest in western medicine. This review summarizes preclinical and clinical studies on the role of the endocannabinoid system and exogenous cannabinoids in anaesthesia and pain management. RECENT FINDINGS: It has recently been shown that the endocannabinoid system is involved in the effects of the widely used anaesthetic drug propofol. In terms of nociception, preclinical data suggest that the endocannabinoid system plays an important role in the control of synaptic transmission and synaptic plasticity in pain pathways. In patients, the treatment of acute pain often requires relatively high doses of cannabinoids, which are associated with considerable side-effects such as dizziness and sedation. In contrast, preclinical and clinical data suggest that lower doses of cannabinoids may be effective for the treatment of allodynia and hyperalgesia in neuropathic pain. In multiple sclerosis, cannabinoids have been shown to have beneficial effects on spasticity, pain, tremor and bladder dysfunction. SUMMARY: In general, the results of the very few well-conducted clinical trials often diverge from the highly interesting and promising findings of preclinical studies. Taken together, the most recent preclinical and clinical data suggest that cannabinoids should be applied as low-dose co-analgesics to inhibit neuroplasticity and central sensitization rather than as analgesics in acute pain.

Journal Article↗

PubMed2003

Integrins in the development, function and dysfunction of the nervous system.

Integrin receptors mediate cell-cell and cell-extracellular matrix (ECM) interactions in many different cell types, including neuronal cells. Earlier studies have shown a clear role for integrins in axon extension and cell adhesion/migration in CNS inflammation. Here we summarize more recent work that shows integrin functions in many phases of neural development, from neuroblast migration to synapse formation. Integrins of the beta-1 and alpha-v family are widely expressed on neurons at many stages of development, and their activity is regulated. Integrins are also important in the adult nervous system, since they have been implicated in synaptic plasticity involved in memory and learning. In addition, several diseases of the nervous system appear to involve beta-1, beta-2, and alpha-v integrins on leukocytes and glial cells. Research challenges for the future include understanding functions of specific integrin heterodimers and identifying the relevant integrin ligands that function in the nervous system.

Animals↗

PubMed2004

Targeting metabotropic glutamate receptors for treatment of the cognitive symptoms of schizophrenia.

Several lines of evidence implicate NMDA receptor dysfunction in the cognitive deficits of schizophrenia, suggesting that pharmacological manipulation of the NMDA receptor may be a feasible therapeutic strategy for treatment of these symptoms. Although direct manipulation of regulatory sites on the NMDA receptor is the most obvious approach for pharmacological intervention, targeting the G-protein coupled metabotropic glutamate (mGlu) receptors may be a more practical strategy for long-term regulation of abnormal glutamate neurotransmission. Heterogeneous distribution, both at structural and synaptic levels, of at least eight subtypes of mGlu receptors suggests that selective pharmacological manipulation of these receptors may modulate glutamatergic neurotransmission in a regionally and functionally distinct manner. Two promising targets for improving cognitive functions are mGlu5 or mGluR2/3 receptors, which can modulate the NMDA receptor-mediated signal transduction by pre- or postsynaptic mechanisms. Preclinical studies indicate that activation of these subtypes of mGlu receptors may be an effective strategy for reversing cognitive deficits resulting form reduced NMDA receptor mediated neurotransmission.

Animals↗

PubMed2004

Learning and memory impairment in rats with chronic atypical absence seizures.

Atypical absence seizures (AASs) represent a pediatric malignant seizure type that commonly exists as a component of Lennox-Gastaut syndrome. AAS involves both the hippocampal and thalamocortical circuitry in slow spike-and-wave discharges (SSWD) and is associated with cognitive dysfunction. The electrographic, behavioral, and pharmacological features of clinical AAS have been reproduced in rats chronically in the AY-9944 (AY) model. AY rats show spontaneous SSWD involving the hippocampus, a structure that is highly implicated in learning and memory. The purpose of the present study was to determine whether AY rats exhibit cognitive deficits that mirror those observed in AAS clinically. Hippocampal function was examined in AY animals both in vitro with electrophysiology (i.e., synaptic plasticity) and in vivo with a hippocampus-dependent radial arm maze (RAM) task that is designed to assess spatial cognition. In vitro tests of synaptic plasticity revealed impairments in long-term potentiation (LTP), paired-pulse facilitation (PPF), and presynaptic depression (PD). Consistently, performance of AY animals in RAM revealed fewer perfect entries, a greater number of errors, and required more training days to learn the task than saline-treated controls. The abolishment of spontaneous seizures by ethosuximide failed to recover the perturbed spatial learning and working memory in AY animals. AY rats demonstrate altered hippocampal functioning as manifested by altered synaptic plasticity and cognition. The relationship between AAS and cognitive deficit remains uncertain and the pathophysiology of both in AY treated requires further investigation.

Animals↗

PubMed2006

Abnormal modulation of cholinergic neurotransmission by endomorphin 1 and endomorphin 2 in isolated bronchus of type 1 diabetic rats.

To assess whether diabetes alters the regulatory effects of mu-opioid receptor (MOR) agonists on the cholinergic bronchoconstriction, we investigated the inhibitory effects of endomorphins (EMs) on the electrical field stimulation (EFS)-induced cholinergic bronchoconstriction in type 1 diabetic rats. At 4 weeks after the onset of diabetes, both the EFS- and exogenous acetylcholine (ACh)-induced bronchoconstriction in diabetes in vitro were greater than those in non-diabetes rats. Furthermore, endomorphin 1 (EM1) and endomorphin 2 (EM2) inhibited the response to EFS in diabetic rat isolated bronchus in a concentration- and frequency-dependent manner, which is in agreement with that in non-diabetes. However, the inhibitory effects of EMs on the EFS-induced bronchoconstriction in diabetes were significantly weaker than those in non-diabetes. Both EM1 and EM2 (1 microM) had no effect on the contractile response to exogenous ACh, indicating a prejunctional effect. Furthermore, the inhibitory effect on the EFS-induced bronchoconstriction was blocked by naloxone (10 microM). Eight weeks after the induction of diabetes, both the EFS- and exogenous ACh-induced bronchoconstrictions in diabetes were further enhanced compared to those in short-time (4 weeks) diabetic rats. Moreover, the inhibitory effects of EMs on the EFS-induced bronchoconstriction were further attenuated. These results suggest that dysfunction of presynaptic inhibitory modulation through opioid receptor by EMs may take place in the bronchus of diabetic rats.

Acetylcholine↗

PubMed1999

Suggestive evidence for inhibitory effects of galanin on mesolimbic dopaminergic neurotransmission.

The objective was to examine effects of galaninrat on forebrain monoamine synthesis and on spontaneous locomotor activity in the rat. The rate of monoamine synthesis was estimated by measuring the accumulation of l-DOPA and 5-HTP, following inhibition of cerebral aromatic l-amino acid decarboxylase by means of NSD-1015 (100 mg kg-1 i.p.), after i.c.v. or intracerebral administration of galanin in adult male Wistar rats. Spontaneous locomotor activity was observed in an automated open-field arena ( approximately 0.5 m2). The i.c.v. administration of galanin (0.5-5.0 nmol bilaterally) produced a dose-dependent, statistically significant, increase in DOPA accumulation throughout the neostriatum, and in the olfactory bulb, indicating an increase in the rate of DA synthesis. No increase was observed in brain areas where noradrenaline is the predominant catecholamine, such as the neocortex or the ventral hippocampus. In addition, there was a tendency for an increase in 5-HTP accumulation in the dorso-lateral neostriatum and in the accumbens. The same i.c.v. administration of galanin produced a dose-dependent, and statistically significant, decrease in spontaneous locomotor activity. The effect on forebrain DA synthesis could also be produced by local bilateral application of galanin (2x1 nmol) into the ventral tegmental area, but not the nucleus accumbens (2x2 nmol). There were no effects on forebrain DOPA or 5-HTP accumulation by the local application of galanin into the locus coeruleus, or into the dorsal raphe nucleus. It is concluded that the neuropeptide galanin modulates forebrain dopaminergic neurotransmission. The effect appears to be mediated at the somato-dendritic level of the meso-neostriatal pathway, and could perhaps be utilized to normalize perturbations ascribed to dysfunction in this neuronal pathway, such as schizophrenia.

5-Hydroxytryptophan↗

PubMed2002

Role of anti-calcium channel and anti-receptor autoantibodies in autonomic dysfunction in Sjögren's syndrome.

Auto-antibodies cross-reacting with L-type voltage-gated calcium channels (VGCCs) have been described in primary Sjögren's syndrome (pSS), and may mediate the cardiac defects in neonates born to mothers with pSS. L-type VGCCs are also present in autonomically innervated tissues. Therefore, the aim of this project was to investigate a role for anti-VGCC antibodies and antibodies to alpha(1)-adrenoceptors or P(2X)-purinoceptors in the autonomic dysfunction that occurs in pSS. Contraction of the sympathetically innervated vas deferens in response to stimulation of the muscle by an alpha(1)-adrenoceptor agonist (phenylephrine) or a P(2X)-purinoceptor agonist (alpha,beta-methylene ATP) was measured in the absence and presence of 2% serum. Contractions produced by phenylephrine and by alpha,beta-methylene ATP were abolished by nicardipine, demonstrating that they are coupled to calcium influx through L-type VGCCs. Serum from patients with pSS or from healthy controls did not significantly alter the L-type channel-dependent responses of smooth muscle to agonist stimulation. We therefore conclude that pSS serum does not contain autoantibodies that functionally inhibit L-type VGCCs, alpha(1)-adrenoceptors or P(2X)-purinoceptors in smooth muscle and that such autoantibodies cannot explain the autonomic dysfunction in pSS.

Adrenergic alpha-Agonists↗