Variation in opsin genes correlates with signalling ecology in North American fireflies.

Genes underlying signal reception should evolve to maximize signal detection in a particular environment. In animals, opsins, the protein component of visual pigments, are predicted to evolve according to this expectation. Fireflies are known for their bioluminescent mating signals. The eyes of nocturnal species are expected to maximize the detection of conspecific signal colours emitted in the typical low-light environment. This is not expected for species that have transitioned to diurnal activity in bright daytime environments. Here, we test the hypothesis that opsin gene sequence plays a role in modifying firefly eye spectral sensitivity. We use genome and transcriptome sequencing in four firefly species, transcriptome sequencing in six additional species and targeted gene sequencing in 28 other species to identify all opsin genes present in North American fireflies and to elucidate amino acid sites under positive selection. We also determine whether amino acid substitutions in opsins are linked to evolutionary changes in signal mode, signal colour and light environment. We find only two opsins, one long wavelength and one ultraviolet, in all firefly species and identify 25 candidate sites that may be involved in determining spectral sensitivity. In addition, we find elevated rates of evolution at transitions to diurnal activity, and changes in selective constraint on long wavelength opsin associated with changes in light environment. Our results suggest that changes in eye spectral sensitivity are at least partially due to opsin sequence. Fireflies continue to be a promising system in which to investigate the evolution of signals, receptors and signalling environments.

Retigabine, a K(V)7 (KCNQ) potassium channel opener, attenuates L-DOPA-induced dyskinesias in 6-OHDA-lesioned rats.

L-DOPA-induced dyskinesias (LID) represent a severe complication of long-time pharmacotherapy in Parkinson's disease that necessitates novel therapeutics. The acute and chronic effects of K(V)7.2-7.5 channel openers (retigabine, flupirtine) on the severity of LID and parkinsonian signs were examined in comparison to the glutamate receptor antagonist amantadine (positive control) in a rat model of LID. Acute treatment with retigabine (2.5, 5 mg/kg i.p.) and flupirtine (5, 10 mg/kg i.p.) significantly reduced the severity of abnormal involuntary movements (AIM) to a comparable extent as amantadine (20, 40 mg/kg s.c.), but flupirtine delayed the disappearance of AIM. Chronic treatment with retigabine (daily 5 mg/kg i.p. over 19 days combined with l-DOPA 10 mg i.p.) did not prevent or delay the development of LID, but reduced the severity of AIM, while antidyskinetic effects of amantadine (40 mg/kg i.p.) were restricted to the first day of treatment. Retigabine caused sedation and ataxia which declined during the chronic treatment, but did not reduce the antiparkinsonian effects of l-DOPA in these experiments. Acute co-injections of retigabine (5 mg) together with l-DOPA (10 mg/kg) neither reduced the motor performance in the rotarod test nor exerted negative effects on the antiparkinsonian efficacy of l-DOPA in the block and stepping test. Nevertheless, the sedative effects of retigabine may limit its therapeutic potential for the treatment of LID. The present data indicate that K(V)7 channels deserve attention in the research of the pathophysiology of dyskinesias. This article is part of a Special Issue entitled 'Post-Traumatic Stress Disorder'.

Pharmacological and autoradiographic studies on the pathophysiological role of GABA(B) receptors in the dystonic hamster: pronounced antidystonic effects of baclofen after striatal injections.

The GABA(B) receptor (GABA(B)R) agonist baclofen is known to have a beneficial potency in patients who suffer from dystonia, a neurological syndrome characterized by involuntary co-contractions of opposing muscles. The underlying mechanisms of this movement disorder are still unclear. Previous studies in the dt(sz) hamster, an animal model of primary paroxysmal dystonia, revealed alterations of the GABAergic system, including a reduction of striatal GABAergic interneurons and an altered GABA(A) receptor (GABA(A)R) binding in several brain regions. In order to clarify the pathophysiological role of central GABA(B)Rs in the hamster mutant, we performed pharmacological and receptor autoradiographic studies. Systemic administration of the GABA(B)R agonist (R)-baclofen (1.5, 2.5 and 3.5 mg/kg i.p.) produced pronounced antidystonic effects in the dt(sz) hamster. Striatal microinjections of baclofen (0.125, 0.25 and 0.5 microg/0.5 microl) also strongly reduced the severity of dystonia. Single striatal administration of the selective GABA(B)R antagonist CGP 35348 [(3-Aminopropyl)(diethoxymethyl)phosphinic acid, 5 and 10 microg/0.5 microl] did not influence the severity of dystonia, but antagonized the antidystonic effect of baclofen. For receptor autoradiographic studies, [H3]-CGP 54626 ([S-(R*,R*)]-[3-[[1-(3,4-Dichlorophenyl)ethyl]amino]-2-hydroxypropyl](cyclohexylmethyl)phosphinic acid) binding was determined in dt(sz) hamsters in comparison to non-dystonic control hamsters. [H3]-CGP 54626 binding was not altered in motor areas but in some limbic structures of dt(sz) hamsters. In view of the absence of striatal changes in GABA(B) binding, the strong antidystonic effect of baclofen after its striatal microinjection is probably related to a suppression of a pathophysiologically increased synaptic activity.

Antidystonic effects of Kv7 (KCNQ) channel openers in the dt sz mutant, an animal model of primary paroxysmal dystonia.

BACKGROUND AND PURPOSE: Mutations in neuronal Kv7 (KCNQ) potassium channels can cause episodic neurological disorders. Paroxysmal dyskinesias with dystonia are a group of movement disorders which are regarded as ion channelopathies, but the role of Kv7 channels in the pathogenesis and as targets for the treatment have so far not been examined. EXPERIMENTAL APPROACH: In the present study, we therefore examined the effects of the activators of neuronal Kv7.2/7.3 channels retigabine (5, 7.5, 10 mg kg(-1) i.p. and 10, 20 mg kg(-1) p.o.) and flupirtine (10, 20 mg kg(-1) i.p.) and of the channel blocker 10,10-bis(4-pyridinylmethyl)-9(10H)-anthracenone (XE-991, 3 and 6 mg kg(-1) i.p.) in the dt sz mutant hamster, a model of paroxysmal dyskinesia in which dystonic episodes occur in response to stress. KEY RESULTS: Retigabine (10 mg kg(-1) i.p., 20 mg kg(-1) p.o.) and flupirtine (20 mg kg(-1) i.p.) significantly improved dystonia, while XE-991 caused a significant aggravation in the dt sz mutant. The antidystonic effect of retigabine (10 mg kg(-1) i.p.) was counteracted by XE-991 (3 mg kg(-1) i.p.). CONCLUSIONS AND IMPLICATIONS: These data indicate that dysfunctions of neuronal Kv7 channels deserve attention in dyskinesias. Since retigabine and flupirtine are well tolerated in humans, the present finding of pronounced antidystonic efficacy in the dt sz mutant suggests that neuronal Kv7 channel activators are interesting candidates for the treatment of dystonia-associated dyskinesias and probably of other types of dystonias. The established analgesic effects of Kv7 channel openers might contribute to improvement of these disorders which are often accompanied by painful muscle spasms.

Age-related changes in striatal nitric oxide synthase-immunoreactive interneurones in the dystonic dtsz mutant hamster.

The dt(sz) mutant hamster represents a model of paroxysmal dyskinesia in which dystonic episodes can be age-dependently induced by stress. GABAergic interneurones which co-express calcium binding proteins were found to be reduced in the striatum of the dt(sz) mutant. Other types of striatal interneurones have so far not been examined. In the present study, we therefore determined the density of nitric oxide synthase (NOS)-immunoreactive interneurones in the striatum of the dt(sz) mutant in comparison with nondystonic control hamsters. At the age of most marked expression of dystonia (30-40 days of life), the density of NOS-positive interneurones was decreased in the striatum of dt(sz) hamsters (-21%) in comparison with age-matched nondystonic control hamsters. Spontaneous remission of dystonia (age >90 days) coincided with a normalization of the density of NOS-reactive interneurones within the whole striatum of dt(sz) hamsters, but there remained a reduced density in distinct subregions. Together with previous findings the present data indicate that the development of striatal interneurones is retarded in mutant hamsters. The age-related deficit of NOS-reactive interneurones may at least in part contribute to an abnormal activity of striatal GABAergic projection neurones and thereby to the age-dependent dystonic syndrome in the dt(sz) mutant.