Dementia rating and nicotinic receptor expression in the prefrontal cortex in schizophrenia

Martin-Ruiz, Carmen; Haroutunian, Vahram; Long, Philip; Young, Allan H.; Davis, Kenneth L.; Perry, Elaine K.; Court, Jennifer A.

doi:10.1016/s0006-3223(03)00348-2

Cited by 90 publications

(73 citation statements)

References 86 publications

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“…Mutations in the channel region of a4-or b2-subunits have been described in families suffering from autosomal dominant frontal lobe epilepsy, 22 and rare microdeletions of the 15q13.3 segment, which includes the CHRNA7 gene, were reported recently in idiopathic generalized epilepsy. 35 A decrease in the density of nAChRs has been reported in brain disorders such as schizophrenia (in the hippocampus, thalamus and some cortical areas) 36 and Alzheimer's disease (mainly in cortical areas and thalamus), 37 whereas an increase has been reported in the cerebellar cortex and thalamus in autism. 38 Decreased striatal a6b3-receptors have been reported in Parkinson's disease.…”

Section: Neuronal Nachrs Nachr Subunitsmentioning

confidence: 99%

Differential contribution of genetic variation in multiple brain nicotinic cholinergic receptors to nicotine dependence: recent progress and emerging open questions

Greenbaum¹,

Lerer²

2009

Mol Psychiatry

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Nicotine dependence (ND), a major public health challenge, is a complex, multifactorial behavior, in which both genetic and environmental factors have a role. Brain nicotinic acetylcholine receptor (nAChR)-encoding genes are among the most prominent candidate genes studied in the context of ND, because of their biological relevance as binding sites for nicotine. Until recently, most research on the role of nAChRs in ND has focused on two of these genes (encoding the a4-and b2-subunits) and not much attention has been paid to the possible contribution of the other nine brain nAChR subunit genes (a2-a3, a5-a7, a9-a10, b3-b4) to the pathophysiology and genetics of ND. This situation has changed dramatically in the last 2 years during which intensive research had addressed the issue, mainly from the genetics perspective, and has shown the importance of the CHRNA5-CHRNA3-CHRNB4 and CHRNA6-CHRNB3 loci in ND-related phenotypes. In this review, we highlight recent findings regarding the contribution of non-a4/b2-subunit containing nAChRs to ND, based on several lines of evidence: (1) human genetics studies (including linkage analysis, candidate-gene association studies and whole-genome association studies) of several ND-related phenotypes; (2) differential pharmacological and biochemical properties of receptors containing these subunits; (3) evidence from genetically manipulated mice; and (4) the contribution of nAChR genes to ND-related personality traits and neurocognitive profiles. Combining neurobiological genetic and behavioral perspectives, we suggest that genetic susceptibility to ND is not linked to one or two specific nAChR subtype genes but to several. In particular, the a3, a5-6 and b3-4 nAChR subunit-encoding genes may play a much more pivotal role in the neurobiology and genetics of ND than was appreciated earlier. At the functional level, variants in these subunit genes (most likely regulatory) may have independent as well as interactive contributions to the ND phenotype spectrum. We address methodological challenges in the field, highlight open questions and suggest possible pathways for future research.

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Section: Neuronal Nachrs Nachr Subunitsmentioning

confidence: 99%

Differential contribution of genetic variation in multiple brain nicotinic cholinergic receptors to nicotine dependence: recent progress and emerging open questions

Greenbaum¹,

Lerer²

2009

Mol Psychiatry

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“…Accordingly, postmortem studies and pharmacological challenges have reported further evidence of decreased expression levels of a 7 -nAChR in patients with schizophrenia (D'Souza and Markou, 2012;Martin-Ruiz et al, 2003). At the behavioral level, the stimulation of a 7 -nAChR through nicotine intake has been demonstrated to improve working memory and selective attention deficits, and to enhance thalamocortical functional connectivity in schizophrenia patients (Jacobsen et al, 2004;Sacco et al, 2005).…”

Section: Introductionmentioning

confidence: 99%

Smoking Restores Impaired LTD-Like Plasticity in Schizophrenia: a Transcranial Direct Current Stimulation Study

Strube

Bunse

Nitsche

et al. 2014

Neuropsychopharmacol

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Impaired neuroplastic responses following noninvasive brain stimulation have been reported repeatedly in schizophrenia patients. These findings have been associated with deficits in GABAergic, glutamatergic, and cholinergic neurotransmission. Although various neurophysiological studies have indicated a relationship between nicotine and neuroplasticity in healthy individuals, the present study is the first investigation into the impact of nicotine on LTD-like plasticity in patients with schizophrenia. Cortical excitability and cortical plasticity were explored in 30 schizophrenia patients (17 smoker, 13 nonsmoker) and 45 healthy controls (13 smoker, 32 nonsmoker) by using single-pulse transcranial magnetic stimulation (TMS) before and following cathodal transcranial direct current stimulation (tDCS) applied to the left primary motor cortex. Our analysis revealed abolished LTD-like plasticity in nonsmoking schizophrenia patients. However, these plasticity deficits were not present in smoking schizophrenia patients. In healthy controls, significant MEP reductions following cathodal tDCS were observed in nonsmoking individuals, but only trend-level reductions in smokers. In smoking schizophrenia patients, the severity of negative symptoms correlated positively with reduced neuroplasticity, whereas nonsmoking patients displayed the opposite effect. Taken together, the data of our study support the notion of an association between chronic smoking and the restitution of impaired LTD-like plasticity in schizophrenia patients. Although replication and further research are needed to better understand this relationship, our findings indicate that nicotine intake might stabilize the impaired inhibition-facilitation balance in the schizophrenic brain through a complex interaction between cortical plasticity, and GABAergic and cholinergic neurotransmission, and might explain the reduced prevalence of negative symptoms in this population.

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“…Comparison with the one-dimensional 1 H spectrum of NTII revealed almost coinciding envelope for all three one-dimensional spectra, with intact position of several characteristic non-overlapping resonances and with additional signals in the case of chimeras (data not shown). The 1 H-15 N HSQC spectra for recombinant 15 N-labeled NTII and NTII/I (Fig. 3, A and B) revealed almost complete correspondence of 1 H and 15 N resonance frequencies for common residues in both toxins.…”

Section: Construction Of Short/long-chain ␣-Neurotoxin Chimeras-mentioning

confidence: 86%

“…Finally, protein solutions were lyophilized overnight on an Alpha I-5 freeze dryer (Martin Christ Gefriertrocknungsanlagen GmbH). Protocol for production and purification of 15 N-labeled NTII and NTII/I chimera was the same as in the case of non-labeled toxins, with the exception of using 15 NHCl as a sole source of nitrogen ( 15 N Ͼ 99%; Martek Biosciences). Analysis of Recombinant Toxins-All the steps of protein production, isolation, and purification were controlled by 12% Tris/Tricine-SDS-PAGE (33).…”

Section: Comparison Of Ntii Spatial Structure With Structures Ofmentioning

confidence: 99%

Bacterial Expression, NMR, and Electrophysiology Analysis of Chimeric Short/Long-chain α-Neurotoxins Acting on Neuronal Nicotinic Receptors

Lyukmanova

Шенкарев

Schulga

et al. 2007

Journal of Biological Chemistry

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Different snake venom neurotoxins block distinct subtypes of nicotinic acetylcholine receptors (nAChR). Short-chain ␣-neurotoxins preferentially inhibit muscle-type nAChRs, whereas longchain ␣-neurotoxins block both muscle-type and ␣7 homooligomeric neuronal nAChRs. An additional disulfide in the central loop of ␣-and -neurotoxins is essential for their action on the ␣7 and ␣3␤2 nAChRs, respectively. Design of novel toxins may help to better understand their subtype specificity. To address this problem, two chimeric toxins were produced by bacterial expression, a short-chain neurotoxin II Naja oxiana with the grafted disulfidecontaining loop from long-chain neurotoxin I from N. oxiana, while a second chimera contained an additional A29K mutation, the most pronounced difference in the central loop tip between long-chain ␣-neurotoxins and -neurotoxins. The correct folding and structural stability for both chimeras were shown by 1 H and 1 H-15 N NMR spectroscopy. Electrophysiology experiments on the nAChRs expressed in Xenopus oocytes revealed that the first chimera and neurotoxin I block ␣7 nAChRs with similar potency (IC 50 6.1 and 34 nM, respectively). Therefore, the disulfide-confined loop endows neurotoxin II with full activity of long-chain ␣-neurotoxin and the C-terminal tail in neurotoxin I is not essential for binding. The A29K mutation of the chimera considerably diminished the affinity for ␣7 nAChR (IC 50 126 nM) but did not convey activity at ␣3␤2 nAChRs. Docking of both chimeras to ␣7 and ␣3␤2 nAChRs was possible, but complexes with the latter were not stable at molecular dynamics simulations. Apparently, some other residues and dimeric organization of -neurotoxins underlie their selectivity for ␣3␤2 nAChRs. Nicotinic acetylcholine receptors (nAChRs)2 belong to the class of ligand-gated ion channels (1-3). All nAChRs are composed of five homologous subunits, which span the plasma membrane to form a transmembrane ion-conducting pore. The muscle-type receptors are composed of four types of subunits, ␣2␤␥␦ in the fetal and ␣2␤⑀␦ in the mature receptor. The best studied nAChR of this type is the receptor from electric organ of ray Torpedo marmorata (4). Neuronal receptors consist of two types of subunits, ␣ (␣2-␣10) and ␤ (␤2-␤4), and can have homooligomeric (for example, ␣7-type nAChR) or heterooligomeric (for example, ␣3␤2-type receptor) composition. Neuronal nAChRs are widely expressed both pre-and postsynaptically, and presynaptic receptors modulate synaptic activity and the release of different neurotransmitters. Neuronal nAChRs are found also in non-neuronal tissues, such as keratinocytes and pulmonary and other tissues (5-8).Because of their role in cellular communication, nAChRs play important roles in the normal functioning of the organism. Dysfunctions of these receptors have been proposed to contribute to a number of disorders of the central and peripheral nervous systems such as schizophrenia, epilepsy, depression, nicotine and alcohol dependence, Alzheimer disease, Parkinson disease, and autis...

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Dementia rating and nicotinic receptor expression in the prefrontal cortex in schizophrenia

Cited by 90 publications

References 86 publications

Differential contribution of genetic variation in multiple brain nicotinic cholinergic receptors to nicotine dependence: recent progress and emerging open questions

Differential contribution of genetic variation in multiple brain nicotinic cholinergic receptors to nicotine dependence: recent progress and emerging open questions

Smoking Restores Impaired LTD-Like Plasticity in Schizophrenia: a Transcranial Direct Current Stimulation Study

Bacterial Expression, NMR, and Electrophysiology Analysis of Chimeric Short/Long-chain α-Neurotoxins Acting on Neuronal Nicotinic Receptors

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