Alpha7 Neuronal Nicotinic Acetylcholine Receptor Research Articles

Activation of alpha-7 nicotinic acetylcholine receptor by tropisetron mitigates 3-nitropropionic acid-induced Huntington's disease in rats: Role of PI3K/Akt and JAK2/NF-κB signaling pathways

Huntington's disease (HD) is an inheritable autosomal-dominant disorder that targets mainly the striatum. 3-Nitropropionic acid (3-NP) induces obvious deleterious behavioral, neurochemical, and histological effects similar to the symptoms of HD. Our study aimed to examine the neuroprotective activity of tropisetron, an alpha-7 neuronal nicotinic acetylcholine receptor (α-7nAChR) agonist, against neurotoxic events associated with 3-NP-induced HD in rats. Forty-eight rats were randomly allocated into four groups. Group I received normal saline, while Groups II, III and IV received 3-NP for 2 weeks. In addition, Group III and IV were treated with tropisetron 1 h after 3-NP administration. Meanwhile, Group IV received methyllycaconitine (MLA), an α-7nAChR antagonist, 30 min before tropisetron administration. Treatment with tropisetron improved motor deficits as confirmed by the behavioral tests and restored normal histopathological features of the striatum. Moreover, tropisetron showed an anti-oxidant activity via increasing the activities of SDH and HO-1 as well as Nrf2 expression along with reducing MDA level. Tropisetron also markedly upregulated the protein expression of p-PI3K and p-Akt which in turn hampered JAK2/NF-κB inflammatory cascade. In addition, tropisetron showed an anti-apoptotic activity through boosting the expression of Bcl-2 and reducing Bax expression and caspase-3 level. Interestingly, all the aforementioned effects of tropisetron were blocked by pre-administration of MLA, which confirms that such neuroprotective effects are mediated via activating of α-7nAChR. In conclusion, tropisetron showed a neuroprotective activity against 3-NP-induced HD via activating PI3K/Akt signaling and suppressing JAK2/NF-κB inflammatory axis. Thus, repositioning of tropisetron could represent a promising therapeutic strategy in management of HD.

Exploring the ameliorative role of α7 neuronal nicotinic acetylcholine receptor modulation in epilepsy and associated comorbidities in post-PTZ-kindled mice

AimThe present study aimed to explore the ameliorative role of alpha7 (α7) neuronal nicotinic acetylcholine receptor (nAChR) modulation in epilepsy and associated comorbidities in postpentylenetetrazole (PTZ)-kindled mice. Material and methodsThe subconvulsive dose of PTZ (35 mg/kg, i.p.) was used to induce kindling-associated epileptogenesis in mice. After successful kindling, animals were treated intraperitoneally with saline, phenytoin (35 mg/kg), valproate (300 mg/kg), choline chloride (α7 agonist; 400 mg/kg and 800 mg/kg), and methyllycaconitine citrate (α7 antagonist; 3.5 mg/kg and 7.0 mg/kg) for 10 days. All the groups except naive were exposed to PTZ injections on day 3, 6, and 9 of treatment to assess seizure severity score. Epilepsy-associated comorbid depression was evaluated by tail suspension test, sucrose preference test, and plasma corticosterone levels, whereas epilepsy-associated memory deficit condition was assessed by step-through paradigm, Morris water maze, and nitrite levels. Neurochemical perturbations related to epilepsy and associated depression and memory deficit were measured by high-performance liquid chromatography (HPLC). ResultsPost-PTZ-kindled mice displayed significant depressive behavior and memory impairment as compared with naive mice as evidenced by corresponding behavioral and biochemical observations. Methyllycaconitine citrate treatment was unable to produce any ameliorative effect in diseased condition. Choline administration dose dependently ameliorated depression, memory impairment, and seizure severity in post-PTZ-kindled mice. The behavioral findings of the study were concurred with neurochemical and biochemical findings. ConclusionIn conclusion, the present study demonstrated the amelioration of epilepsy, comorbid depression, and memory deficit by α7 nAChR agonist choline chloride in PTZ-kindled mice model.

CHRFAM7A alters binding to the neuronal alpha-7 nicotinic acetylcholine receptor

IntroductionCHRFAM7A is a uniquely-human gene that encodes a human-specific variant of the alpha-7 nicotinic acetylcholine receptor (α7nAchR). While the homopentameric α7nAChR consists of 5 equal subunits, previous studies demonstrated that CHRFAM7A expression disrupts the formation of α7nAChR homopentamers. Here we use a rat neuronal cell line expressing CHRFAM7A and a transgenic mouse expressing CHRFAM7A to define the alpha-bungarotoxin (α-BTX) binding in vitro and in vivo. MethodsRat PC12 cells were stably transfected with human CHRFAM7A. α-BTX, a protein that irreversibly binds the α7nAchR, was utilized to assess the capacity for CHRFAM7A to interfere with α 7AchR subunits using immunohistochemistry and flow cytometry. To evaluate the effects of CHRFAM7A on α7nAchR at the neuromuscular junction in vivo, transgenic mice were engineered to express the uniquely human gene CHRFAM7A under the control of the EF1-α promoter. Using this model, muscle was harvested and CHRFAM7A and CHRNA7 gene expression evaluated by PCR. Binding of α-BTX to the α7nAchR in muscle was compared in sibling-matched wild-type C57 mice by immunostaining the neuromuscular junction using α-BTX and neurofilament antibodies. ResultsExpression of CHRFAM7A in transfected, but not vector cells, was confirmed by PCR and by immunoblotting using an antibody we raised to a peptide sequence unique to CHRFAM7A. CHRFAM7A decreased α-BTX binding as detected by immunohistochemistry and flow cytometry. In vivo, α-BTX co-stained with neurofilament at the neuromuscular junction in wild-type mice, however, α-BTX staining was decreased at the neuromuscular junction of CHRFAM7A transgenic mice. ConclusionCHRFAM7A expression interferes with the binding of α7nAchR to α-BTX. Understanding the contribution of this uniquely human gene to human disease will be important in the identification of potential therapeutic targets.

Copy number variations in healthy subjects. Case study: iPSC line CSSi005-A (3544) production from an individual with variation in 15q13.3 chromosome duplicating gene CHRNA7

CHRNA7, encoding the neuronal alpha7 nicotinic acetylcholine receptor (a7nAChR), is highly expressed in the brain, particularly in the hippocampus. It is situated in the 15q13.3 chromosome region, frequently associated with a Copy Number Variation (CNV), which causes its duplication or deletion. The clinical significance of CHRNA7 duplications is unknown so far, but there are several research data suggesting that they may be pathogenic, with reduced penetrance. We have produced an iPS cell line from a single healthy donor's fibroblasts carrying a 15q13.3 CNV, including CHRNA7 in order to study the exact role of this CNV during the neurodevelopment.

The Cholinergic Anti-Inflammatory Response and the Role of Macrophages in HIV-Induced Inflammation.

Macrophages are phagocytic immune cells that protect the body from foreign invaders and actively support the immune response by releasing anti- and proinflammatory cytokines. A seminal finding revolutionized the way macrophages are seen. The expression of the neuronal alpha7 nicotinic acetylcholine receptor (α7-nAChR) in macrophages led to the establishment of the cholinergic anti-inflammatory response (CAR) in which the activation of this receptor inactivates macrophage production of proinflammatory cytokines. This novel neuroimmune response soon began to emerge as a potential target to counteract inflammation during illness and infection states. Human immunodeficiency virus (HIV)-infected individuals suffer from chronic inflammation that persists even under antiretroviral therapy. Despite the CAR’s importance, few studies involving macrophages have been performed in the HIV field. Evidence demonstrates that monocyte-derived macrophages (MDMs) recovered from HIV-infected individuals are upregulated for α7-nAChR. Moreover, in vitro studies demonstrate that addition of an HIV viral constituent, gp120IIIB, to uninfected MDMs also upregulates the α7-nAChR. Importantly, contrary to what was expected, activation of upregulated α7-nAChRs in macrophages does not reduce inflammation, suggesting a CAR disruption. Although it is reasonable to consider this receptor as a pharmacological target, additional studies are necessary since its activity seems to differ from that observed in neurons.

Pharmacological Properties and Evaluations of a Novel Positive Allosteric Modulator of α7 nAChR for Attenuation of Schizophrenia-Like Behavior in Mice

The alpha-7 neuronal nicotinic acetylcholine receptor (α7 nAChR), consisting of homomeric α7 subunits, is a ligand-gated Ca2+-permeable ion channel critical for cognition, sensory processing, attention, and working memory. Dysfunctional α7 nAChR is implicated in cognition and neuropsychiatric disorders. Therefore, enhancement of α7 nAChR function is considered to be therapeutic strategy aimed at ameliorating cognitive deficits of neuropsychiatric disorders such as Alzheimer's disease (AD) and schizophrenia. We recently synthesized a novel series of 6-(2-Chloro-6-methylphenyl)-2-((3-fluoro-4-methylphenyl)amino)thiazolo[4,5-d]pyrimidin-7(6H)-ones as positive allosteric modulators (PAM) of α7 nAChR. In this study we evaluated the effect of a representative compound JWX-A0108 on activation of α7 and auditory gating or cognitive deficits in mice using a combination of assays including two-electrode voltage clamp (TEVC) recordings of Xenopus oocytes expressing human α7 nAChR, brain slice recordings, pre-pulse inhibition (PPI) for startle response and Y-maze spontaneous alternation test. Compound JWX-A0108 exhibits as type I PAM that specifically activates α7 current in the presence of 100 µM ACh in dose-dependent manner with EC50 at 5.7 ± 0.7 µM and 6-fold increase of the current. Application of JWX-A0108 (1-10 mg/kg, i.p.) dose-dependently reversed the auditory gating deficit induced by NMDA antagonist MK-801 in prepulse inhibition assay. In Y-maze, JWX-A0108 (0.03-0.3 mg/kg, i.p.) significantly increased the time spent in novel arm from 45% to 63% in mice treated with MK-801. We also evaluated the effect of JWX-A0108 on locomotor activity, and fount that JWX-A0108 (0.03 mg/kg, i.p.) significantly reduced MK-801-induced hyperactivity. The effects of JWX-A0108 on selectivity, pERK signaling and synaptic transmissions are currently being investigated.

A novel prophylactic effect of furosemide treatment on autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE)

The transgenic rat strain S284L-TG harbors the S284L mutant of the neuronal nicotinic acetylcholine receptor alpha4 subunit gene (CHRNA4), which is responsible for human autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE). S284L-TG rats have epileptic seizure phenotypes during slow-wave sleep, similar to those in NFLE. We previously demonstrated that γ-aminobutyric acid (GABA)ergic action of these rats was suppressed before the onset of ADNFLE seizures, and that glutamate release in the epileptic focus lesion was increased at the onset of epilepsy. Here, mRNA analysis revealed that Cl(-)-accumulating Na-K-2Cl cotransporter 1 (NKCC1) levels were increased and Cl(-)-extruding K-Cl cotransporter 1 and 2 (KCC1 and KCC2) levels were decreased at the onset of ADNFLE seizures in S284L-TG rat frontal cortexes, which perturbed the GABAergic inhibitory system. The reversal potentials (EGABA) of GABAA receptor-mediated currents in cortical layer V pyramidal neurons of S284L-TG rats also changed their polarity from hyperpolarization to depolarization, and S284L-TG miniature excitatory postsynaptic currents (mEPSCs), but not miniature inhibitory postsynaptic currents (mIPSCs), significantly increased in both amplitude and frequency. Administration of 25mg/kg/day furosemide before, but not after, the onset of interictal discharges prevented idiopathic epileptic activity, reversed the depolarizing shift of EGABA and increased mEPSC amplitude to normal levels. These data indicate that early treatment with an agent that normalizes pathogenesis has a prophylactic effect on epilepsy. We propose a strategy for prophylactic medication against idiopathic epilepsy through the suppression of epileptogenesis and/or ictogenesis.

Preclinical characterization of a selective alpha-7 neuronal nicotinic acetylcholine receptor agonist ABT-126: A novel therapeutic agent for the treatment of cognitive impairment in Alzheimer's disease and schizophrenia

Preclinical characterization of a selective alpha-7 neuronal nicotinic acetylcholine receptor agonist ABT-126: A novel therapeutic agent for the treatment of cognitive impairment in Alzheimer's disease and schizophrenia

A New View on Allosteric Modulation of Alpha 7 Nicotinic Acetylcholin Receptors

Nicotinic acetylcholine receptors (nAChR) are ligand gated cation channels that are opened by agonists like Acetylcholine and Nicotine. They are widely distributed in neurons all over central nervous system, where they are mainly found at postsynaptic locations of cholinergic nerve endings.The most abundant homomeric nicotinic acetylcholine receptors in the mammalian brain are the pentameric alpha7 nAChRs which consist of five alpha7 subunits. Each subunit provides an orthosteric low affinity binding site for its endogenous ligand, acetylcholine. Several lines of evidence suggest a link between the alpha7 neuronal nicotinic acetylcholine receptor and brain disorders including schizophrenia, Alzheimer's disease, and traumatic brain injury. Alpha 7 receptors are also a target for non-CNS indications like diabetes and asthma.View Large Image | View Hi-Res Image | Download PowerPoint SlideHere we show the results of the screen of allosteric modulators on alpha 7 receptors. High parallelization without a compromise in data quality combined with fast and accurate solution exchange allows characterization of many compounds. A second analysis at physiological temperatures showed a pronounced effect on the allosteric modulation.

Association of CHRNA4 polymorphism with depression and loneliness in elderly males

The cholinergic receptor, nicotinic, alpha 4 (CHRNA4) gene encodes the neuronal nicotinic acetylcholine receptor alpha-4 subunit. Recent research has shown that a variation in CHRNA4 (rs1044396) affects attention and negative emotionality in normal adults. To determine the link between CHRNA4 variation and cognitive function/depressed mood, this study conducted a genotype-phenotype correlation analysis between the common CHRNA4:rs1044396 variant and several baseline parameters of cognition and depressed mood in 192 elderly male subjects without major psychiatric disorders or dementia. Study findings identified a significant link between the CHRNA4:rs1044396 polymorphism and depression and loneliness in the aged. Compared to carriers of at least one T-allele, carriers of the homozygous C/C genotype described themselves as more depressed and lonely. This is the first evidence which may implicate CHRNA4 in depressed emotions in the elderly.

Familial frontal lobe epilepsy and its relationship with other nocturnal paroxysmal events

Familial frontal lobe epilepsy and its relationship with other nocturnal paroxysmal events

Alpha7 nicotinic acetylcholine receptor agonists: Prediction of their binding affinity through a molecular mechanics Poisson–Boltzmann surface area approach

A group of agonists for the alpha7 neuronal nicotinic acetylcholine receptors (nAChRs) was investigated, and their free energies of binding DeltaG(bind) were calculated by applying the molecular mechanics Poisson-Boltzmann surface area (MM-PBSA) approach. This method, based on molecular dynamics simulations of fully solvated protein-ligand complexes, allowed us to estimate the contribution of both polar and nonpolar terms as well as the entropy to the overall free energy of binding. The calculated results were in a good agreement with the experimentally determined DeltaG(bind) values, thereby pointing to the MM-PBSA protocol as a valuable computational tool for the rational design of specific agents targeting the neuronal alpha7 nAChR subtypes.

Discovery ofN-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]furo[2,3-c]pyridine-5-carboxamide, an Agonist of the α7 Nicotinic Acetylcholine Receptor, for the Potential Treatment of Cognitive Deficits in Schizophrenia: Synthesis and Structure−Activity Relationship

N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]furo[2,3-c]pyridine-5-carboxamide (14, PHA-543,613), a novel agonist of the alpha7 neuronal nicotinic acetylcholine receptor (alpha7 nAChR), has been identified as a potential treatment of cognitive deficits in schizophrenia. Compound 14 is a potent and selective alpha7 nAChR agonist with an excellent in vitro profile. The compound is characterized by rapid brain penetration and high oral bioavailability in rat and demonstrates in vivo efficacy in auditory sensory gating and, in an in vivo model to assess cognitive performance, novel object recognition.

Unexpected sensitivity of the human α7 neuronal nicotinic acetylcholine receptor to aminoglycosides

The wide use of antibiotics and the development of resistance is a major health concern and, despite their relatively severe side effects, aminoglycoside antibiotics are still used in clinics. Effects of seven aminoglycosides were investigated at the human homomeric alpha7 and heteromeric alpha4beta2 neuronal nicotinic acetylcholine receptors. All aminoglycosides tested inhibited the acetylcholine-evoked responses with more pronounced effects at alpha7 than at alpha4beta2. Neomycin displayed higher blockade with a half inhibition in the nanomolar range at low calcium concentration and in the micromolar range in physiological calcium concentration but still exerted blockade below the concentration used in the clinic. These data suggest that some of their side effects may be attributable to their interactions with neuronal nicotinic acetylcholine receptors.

Subtype-specific actions of beta-amyloid peptides on recombinant human neuronal nicotinic acetylcholine receptors (alpha7, alpha4beta2, alpha3beta4) expressed in Xenopus laevis oocytes.

Two-electrode voltage-clamp electrophysiology has been used to study the actions of two amyloid peptides (Abeta(1-42), Abeta(1-40)) on alpha7, alpha4beta2 and alpha3beta4 recombinant human neuronal nicotinic acetylcholine receptors (nicotinic AChRs), heterologously expressed in Xenopus laevis oocytes. The application of Abeta(1-42) or Abeta(1-40) (1 pM-100 nM) for 5 s does not directly activate expressed human alpha7, alpha4beta2 or alpha3beta4 nicotinic AChRs.Abeta(1-42) and Abeta(1-40) are antagonists of alpha7 nicotinic AChRs. For example, 10 nM Abeta(1-42) and Abeta(1-40) both reduced the peak amplitude of currents recorded (3 mM ACh) to 48+/-5 and 45+/-10% (respectively) of control currents recorded in the absence of peptide. In both the cases the effect is sustained throughout a 30 min peptide application and is poorly reversible.Abeta(1-42) and Abeta(1-40) (10 nM) enhance currents recorded in response to ACh (3 mM) from oocytes expressing alpha4beta2 nicotinic AChRs by 195+/-40 and 195+/-41% respectively. This effect is transient, reaching a peak after 3 min and returning to control values after a 24 min application of 10 nM Abeta(1-42). We observe an enhancement of 157+/-22% of control ACh-evoked current amplitude in response to 100 nM Abeta(1-42) recorded from oocytes expressing alpha4beta2 nicotinic AChRs.Abeta(1-42) and Abeta(1-40) (10 nM) were without antagonist actions on the responses of alpha3beta4 nicotinic AChRs to ACh (1 nM-3 mM).

Structural Dynamics of the α-Neurotoxin−Acetylcholine-Binding Protein Complex: Hydrodynamic and Fluorescence Anisotropy Decay Analyses

The three-fingered alpha-neurotoxins have played a pivotal role in elucidating the structure and function of the muscle-type and neuronal alpha7 nicotinic acetylcholine receptors (nAChRs). To advance our understanding of the alpha-neurotoxin-nAChR interaction, we examined the flexibility of alpha-neurotoxin bound to the acetylcholine-binding protein (AChBP), which shares structural similarity and sequence identities with the extracellular domain of nAChRs. Because the crystal structure of five alpha-cobratoxin molecules bound to AChBP shows the toxins projecting radially like propeller "blades" from the perimeter of the donut-shaped AChBP, the toxin molecules should increase the frictional resistance and thereby alter the hydrodynamic properties of the complex. alpha-Bungarotoxin binding had little effect on the frictional coefficients of AChBP measured by analytical ultracentrifugation, suggesting that the bound toxins are flexible. To support this conclusion, we measured the anisotropy decay of four site-specifically labeled alpha-cobratoxins (conjugated at positions Lys(23), Lys(35), Lys(49), and Lys(69)) bound to AChBP and free in solution and compared their anisotropy decay properties with fluorescently labeled cysteine mutants of AChBP. The results indicated that the core of the toxin molecule is relatively flexible when bound to AChBP. When hydrodynamic and anisotropy decay analyses are taken together, they establish that only one face of the second loop of the alpha-neurotoxin is immobilized significantly by its binding. The results indicate that bound alpha-neurotoxin is not rigidly oriented on the surface of AChBP but rather exhibits segmental motion by virtue of flexibility in its fingerlike structure.

Lack of an association between candidate gene loci and idiopathic generalized epilepsy in Kuwaiti Arab children

Idiopathic generalized epilepsies (IGEs) are the most common types of epilepsy in childhood and adolescence. A variety of data suggest that IGEs have a predominant genetic etiology. Recently, a number of gene mutations have been found to be associated with various types of epilepsy in mainly the Caucasian populations. The objective of this study was to investigate the association of three different candidate genes with IGE in Kuwaiti Arab children. This study includes 123 Kuwaiti patients with a confirmed diagnosis of epilepsy. Most of the patients have had a diagnostic EEG with generalized spike-wave discharges (GSWs). All patients were evaluated by using a validated seizure questionnaire. The clinical type of epilepsy was determined by a trained neurologist/pediatrician. The study also include 100 controls, the control subjects were children which did not have any history of neurological disorders. Blood samples were collected from all patients and control subjects after taking informed consent. DNA was isolated and analyzed by molecular methods. A FokI polymorphism in neuronal nicotinic acetylcholine receptor alpha-4 subunit (CHRNA4) gene was detected by PCR-RFLP method. A missense mutation (Ser248Phe) in CHRNA4 gene was analyzed by PCR-RFLP using HpaII. A C121W mutation in sodium-channel beta-1 subunit (SCN1B) gene was screened by a PCR-RFLP method using HinPI. A 2-bp deletion in Cystatin B gene was detected by PCR-RFLP using XcmI. The incidence of three FokI polymorphism genotypes in Kuwaiti IGE patients was 1,1 (85%), 1,2 (14%) and 2,2 (1%) respectively. The missense mutation Ser248Phe of CHRNA4 gene was not detected at all in Kuwaiti IGE patients. The C387G transversion resulting in C121W change in third exon of the SCN1B gene was detected in 3/123 patients (2%). The patients carrying this mutation also exhibited febrile seizures. The incidence of 2 bp deletion in the cystatin B gene was found to be 4% (5/123 IGE patients). The data obtained from molecular analysis show a lack of association between three candidate genes and clinical expression of IGE in Kuwaiti Arab children. This is completely different from the findings reported from Caucasian populations of France, Australia and USA in which case a strong association has been reported between IGE and these genes.

Effect of galantamine on the human α7 neuronal nicotinic acetylcholine receptor, the Torpedo nicotinic acetylcholine receptor and spontaneous cholinergic synaptic activity

1. Various types of anticholinesterasic agents have been used to improve the daily activities of Alzheimer's disease patients. It was recently demonstrated that Galantamine, described as a molecule with anticholinesterasic properties, is also an allosteric enhancer of human alpha4beta2 neuronal nicotinic receptor activity. We explored its effect on the human alpha7 neuronal nicotinic acetylcholine receptor (nAChR) expressed in Xenopus oocytes. 2. Galantamine, at a concentration of 0.1 microM, increased the amplitude of acetylcholine (ACh)-induced ion currents in the human alpha7 nAChR expressed in Xenopus oocytes, but caused inhibition at higher concentrations. The maximum effect of galantamine, an increase of 22% in the amplitude of ACh-induced currents, was observed at a concentration of 250 microM Ach. 3. The same enhancing effect was obtained in oocytes transplanted with Torpedo nicotinic acetylcholine receptor (AChR) isolated from the electric organ, but in this case the optimal concentration of galantamine was 1 microM. In this case, the maximum effect of galantamine, an increase of 35% in the amplitude of ACh-induced currents, occurred at a concentration of 50 microM ACh. 4. Galantamine affects not only the activity of post-synaptic receptors but also the activity of nerve terminals. At a concentration of 1 microM, quantal spontaneous events, recorded in a cholinergic synapse, increased their amplitude, an effect which was independent of the anticholinesterasic activity associated with this compound. The anticholinesterasic effect was recorded in preparations treated with a galantamine concentration of 10 microM. 5. In conclusion, our results show that galantamine enhances human alpha7 neuronal nicotinic ACh receptor activity. It also enhances muscular AChRs and the size of spontaneous cholinergic synaptic events. However, only a very narrow range of galantamine concentrations can be used for enhancing effects.

A Korean kindred with autosomal dominant nocturnal frontal lobe epilepsy and mental retardation.

A Korean family had distinctive clinical and neuroimaging features and carried the same genetic mutation that was found in a previously described Japanese kindred with autosomal dominant nocturnal frontal lobe epilepsy. To describe the first Korean family with autosomal dominant nocturnal frontal lobe epilepsy. Members of a large family, including 9 affected individuals from 3 generations, underwent a comprehensive genetic, clinical, electroencephalographic, neuropsychological, and neuroimaging evaluation. Affected members were tested for possible mutations in transmembrane regions 1 through 3 of the neuronal nicotinic acetylcholine receptor alpha4 subunit (CHRNA4) by direct sequencing and subsequent restriction analysis. Seizures began in childhood, presenting as nocturnal episodes of staring, confusion, shouting, perioral movements, unintelligible speech, and hand waving. Some patients had ictal or interictal epileptiform activity in the temporal and/or frontocentral areas. Neurological examination and brain magnetic resonance imaging results showed no abnormalities, except that all patients available for testing had mild to moderate mental retardation. Fluorodeoxyglucose F 18 with positron emission tomography showed mild decreased glucose uptake in the superior and middle frontal regions, more so on the left than on the right. Patient response to carbamazepine was poor. All affected members were heterozygous for the CHRNA4 Ser252Leu mutation. Disorders associated with mutations in the transmembrane region 2 of CHRNA4 are genetically and phenotypically heterogeneous. Distinctive features of this kindred include (1) mental retardation in all affected members available for testing, (2) abnormal brain findings on fluorodeoxyglucose F 18 with positron emission tomography, (3) poor response to carbamazepine, and (4) full penetrance.

Analysis of variants in the promoter of the human alpha7 neuronal nicotinic acetylcholine receptor

Analysis of variants in the promoter of the human alpha7 neuronal nicotinic acetylcholine receptor