Autosomal dominant nocturnal frontal lobe epilepsy

Combi, Romina; Dalprà, Leda; Tenchini, Maria Luisa; Ferini‐Strambi, Luigi

doi:10.1007/s00415-004-0541-x

Cited by 130 publications

(95 citation statements)

References 106 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…(1) ADNFLE seizures are typically characterized by repetitive jerky limb movements and asymmetrical posturing (for review, see Combi et al, 2004). Nicotine seizures in L9ЈA mice consist of forelimb clonus and loss of righting response (which can also be described as asymmetrical posturing).…”

Section: Similarities With Adnflementioning

confidence: 99%

See 1 more Smart Citation

Novel Seizure Phenotype and Sleep Disruptions in Knock-In Mice with Hypersensitive α4^*Nicotinic Receptors

Fonck¹,

Cohen²,

Nashmi³

et al. 2005

J. Neurosci.

120

View full text Add to dashboard Cite

A leucine to alanine substitution (L9ЈA) was introduced in the M2 region of the mouse ␣4 neuronal nicotinic acetylcholine receptor (nAChR) subunit. Expressed in Xenopus oocytes, ␣4(L9ЈA)␤2 nAChRs were Ն30-fold more sensitive than wild type (WT) to both ACh and nicotine. We generated knock-in mice with the L9ЈA mutation and studied their cellular responses, seizure phenotype, and sleepwake cycle. Seizure studies on ␣4-mutated animals are relevant to epilepsy research because all known mutations linked to autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) occur in the M2 region of ␣4 or ␤2 subunits. Thalamic cultures and synaptosomes from L9ЈA mice were hypersensitive to nicotine-induced ion flux. L9ЈA mice were ϳ15-fold more sensitive to seizures elicited by nicotine injection than their WT littermates. Seizures in L9ЈA mice differed qualitatively from those in WT: L9ЈA seizures started earlier, were prevented by nicotine pretreatment, lacked EEG spike-wave discharges, and consisted of fast repetitive movements. Nicotine-induced seizures in L9ЈA mice were partial, whereas WT seizures were generalized. When L9ЈA homozygous mice received a 10 mg/kg nicotine injection, there was temporal and phenomenological separation of mutant and WT-like seizures: an initial seizure ϳ20 s after injection was clonic and showed no EEG changes. A second seizure began 3-4 min after injection, was tonic-clonic, and had EEG spike-wave activity. No spontaneous seizures were detected in L9ЈA mice during chronic video/EEG recordings, but their sleep-wake cycle was altered. Our findings show that hypersensitive ␣4* nicotinic receptors in mice mediate changes in the sleep-wake cycle and nicotineinduced seizures resembling ADNFLE.

show abstract

Section: Similarities With Adnflementioning

confidence: 99%

“…parallel between ADNFLE and nicotine seizures in L9ЈA mice is that ϳ70% of ADNFLE patients have nondiagnostic EEGs Oldani et al, 1998;Rozycka et al, 2003) (for review, see Combi et al, 2004). Nicotine seizures in L9ЈA were undetected by EEG.…”

Section: Similarities With Adnflementioning

confidence: 99%

Novel Seizure Phenotype and Sleep Disruptions in Knock-In Mice with Hypersensitive α4^*Nicotinic Receptors

Fonck¹,

Cohen²,

Nashmi³

et al. 2005

J. Neurosci.

120

View full text Add to dashboard Cite

show abstract

“…In particular, S284L was also identified in the sporadic form NFLE (Phillips et al, 2000). All ADNFLE/ NFLE mutations were heterozygous and within the nAChR gating regulator or pore region (Wonnacott, 1997;Combi et al, 2004;Bertrand et al, 2005), and dysfunctions of the corresponding channel have been demonstrated in vitro.…”

Section: Introductionmentioning

confidence: 98%

Rats Harboring S284LChrna4Mutation Show Attenuation of Synaptic and Extrasynaptic GABAergic Transmission and Exhibit the Nocturnal Frontal Lobe Epilepsy Phenotype

et al. 2008

View full text Add to dashboard Cite

Mutations of genes encoding ␣4, ␤2, or ␣2 subunits (CHRNA4, CHRNB2, or CHRNA2, respectively) of nAChR [neuronal nicotinic ACh (acetylcholine) receptor] cause nocturnal frontal lobe epilepsy (NFLE) in human. NFLE-related seizures are seen exclusively during sleep and are characterized by three distinct seizure phenotypes: "paroxysmal arousals," "paroxysmal dystonia," and "episodic wandering." We generated transgenic rat strains that harbor a missense mutation S284L, which had been identified in CHRNA4 in NFLE. The transgenic rats were free of biological abnormalities, such as dysmorphology in the CNS, and behavioral abnormalities. The mRNA level of the transgene (mutant Chrna4) was similar to the wild type, and no distorted expression was detected in the brain. However, the transgenic rats showed epileptic seizure phenotypes during slow-wave sleep (SWS) similar to those in NFLE exhibiting three characteristic seizure phenotypes and thus fulfilled the diagnostic criteria of human NFLE. The therapeutic response of these rats to conventional antiepileptic drugs also resembled that of NFLE patients with the S284L mutation. The rats exhibited two major abnormalities in neurotransmission: (1) attenuation of synaptic and extrasynaptic GABAergic transmission and (2) abnormal glutamate release during SWS. The currently available genetically engineered animal models of epilepsy are limited to mice; thus, our transgenic rats offer another dimension to the epilepsy research field.

show abstract

“…Numerous variations in Cys-loop ligandgated ion channels have been shown to be causative of channelopathies (18,19). A single-nucleotide polymorphism in the human HTR3B gene giving rise to the nonsynonymous variation Y129S in the 5-HT 3B subunit has been identified in very high frequencies in worldwide populations.…”

mentioning

confidence: 99%

High-frequency HTR3B variant associated with major depression dramatically augments the signaling of the human 5-HT _3AB receptor

Krzywkowski

Davies

Feinberg-Zadek

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

The 5-hydroxytryptamine-3 (5-HT3) receptor mediates the fast excitatory neurotransmission of serotonin and is known to mediate the nausea/emesis induced by radio/chemotherapy and anesthetics. A polymorphism encoding the variation Y129S in the 5-HT3B subunit exists in high frequency in the general population and has been shown to be inversely correlated to the incidence of major depression in women. We show that 5-HT3AB(Y129S) receptors exhibit a substantially increased maximal response to serotonin compared with WT receptors in two fluorescence-based cellular assays. In electrophysiological recordings, the deactivation and desensitization kinetics of the 5-HT3AB ( 5-HT3 ͉ ligand-gated ion channel ͉ polymorphism ͉ serotonin ͉ receptor kinetics S erotonin [5-hydroxytryptamine (5-HT)] is a major neurotransmitter in both the CNS and the peripheral nervous system (PNS), where it plays a key role in basic functions such as mood, sleep, appetite regulation, and libido (1). Serotonergic signaling is mediated via a plethora of G protein-coupled receptors, whereas only one serotonin-gated ion channel has been identified: the 5-HT 3 receptor (2).5-HT 3 receptors are expressed in both the CNS and the PNS. Presynaptic 5-HT 3 receptors are known to modulate the synaptic release of various neurotransmitters (3-5), whereas postsynaptic 5-HT 3 receptors are responsible for the fast excitatory response to serotonin (6). The role of the 5-HT 3 receptor in general physiology and pathophysiology is not well established. However, the 5-HT 3 receptor is known to mediate the nausea and emesis caused by radio/chemotherapy and anesthetics (7). Furthermore, 5-HT 3 antagonists have proven effective in the treatment of irritable bowel disease (7). Finally, the 5-HT 3 receptor has been suggested to be involved in anxiety, depression, pain, alcohol dependence, and eating disorders (7,8).The 5-HT 3 receptor is a nonselective cation channel belonging to the superfamily of Cys-loop ligand-gated ion channels that includes receptors for the neurotransmitters ACh, ␥-aminobutyric acid, and glycine. These receptors are pentameric assemblies, where the five subunits form a central ion channel path (9). To date, five 5-HT 3 subunits have been cloned: 5-HT 3A -5-HT 3E (10-12). Transcripts of 5-HT 3A , 5-HT 3B , and 5-HT 3C subunits have been demonstrated in both the CNS and the PNS (11-13), whereas 5-HT 3D and 5-HT 3E transcripts have been detected only in peripheral tissues (12). By using 5-HT 3B -specific antibodies, the existence of the 5-HT 3B subunit in the human hippocampus (14) as well as in the CNS in rodents (15) has been confirmed. Whereas homomeric 5-HT 3A receptors are functional, the other subunits only form functional receptors when coexpressed with 5-HT 3A (11,16). The homomeric 5-HT 3A and the heteromeric 5-HT 3AB receptors are the best characterized 5-HT 3 receptors, whereas the physiological relevance of subunits 5-HT 3c -5-HT 3E has just started to be unraveled. In heterologous expression systems, the 5-HT 3A :5-HT 3B stoichiometry an...

show abstract

Autosomal dominant nocturnal frontal lobe epilepsy

Cited by 130 publications

References 106 publications

Novel Seizure Phenotype and Sleep Disruptions in Knock-In Mice with Hypersensitive α4^*Nicotinic Receptors

Novel Seizure Phenotype and Sleep Disruptions in Knock-In Mice with Hypersensitive α4^*Nicotinic Receptors

Rats Harboring S284LChrna4Mutation Show Attenuation of Synaptic and Extrasynaptic GABAergic Transmission and Exhibit the Nocturnal Frontal Lobe Epilepsy Phenotype

High-frequency HTR3B variant associated with major depression dramatically augments the signaling of the human 5-HT _3AB receptor

Contact Info

Product

Resources

About

Autosomal dominant nocturnal frontal lobe epilepsy

Cited by 130 publications

References 106 publications

Novel Seizure Phenotype and Sleep Disruptions in Knock-In Mice with Hypersensitive α4*Nicotinic Receptors

Novel Seizure Phenotype and Sleep Disruptions in Knock-In Mice with Hypersensitive α4*Nicotinic Receptors

Rats Harboring S284LChrna4Mutation Show Attenuation of Synaptic and Extrasynaptic GABAergic Transmission and Exhibit the Nocturnal Frontal Lobe Epilepsy Phenotype

High-frequency HTR3B variant associated with major depression dramatically augments the signaling of the human 5-HT 3AB receptor

Contact Info

Product

Resources

About

Novel Seizure Phenotype and Sleep Disruptions in Knock-In Mice with Hypersensitive α4^*Nicotinic Receptors

Novel Seizure Phenotype and Sleep Disruptions in Knock-In Mice with Hypersensitive α4^*Nicotinic Receptors

High-frequency HTR3B variant associated with major depression dramatically augments the signaling of the human 5-HT _3AB receptor