Behavioral effects of a deletion in Kcnn2, the gene encoding the SK2 subunit of small-conductance Ca2+-activated K+ channels

Abstract

Small-conductance Ca(2+)-activated potassium (SK) channels are heteromeric complexes of SK alpha-subunits and calmodulin that modulate membrane excitability, are responsible for part of the after-hyperpolarization (AHP) following action potentials, and thus control the firing patterns and excitability of most central neurons. An engineered knockout allele for the SK2 subunit has previously been reported. The hippocampal neurons of these mice lacked the medium latency component of the AHP, but the animals were not described as presenting any overt behavioral phenotype. In this report, we describe a deletion in the 5' region of the Kcnn2 gene encoding the SK2 subunit in the mouse neurological frissonnant (fri) mutant. The frissonnant mutant phenotype is characterized by constant rapid tremor and locomotor instability. It has been suggested, based merely on its phenotype, as a potential model for human Parkinson disease. We used a positional cloning strategy to identify the mutation underlying the frissonnant phenotype. We narrowed the genetic disease interval and identified a 3,441-bp deletion in the Kcnn2 gene, one of the three candidate genes present in the interval. Expression studies showed complete absence of normal Kcnn2 transcripts while some tissue-specific abnormal truncated variants were detected. Intracellular electrophysiological recordings of central vestibular neurons revealed permanent alterations of the AHP and firing behavior that might cause the tremor and associated locomotor deficits. Thus, the fri mutation suggests a new, potentially important physiological role, which had not been described, for the SK2 subunit of small-conductance Ca(2+)-activated potassium channels.

Potential Downstream Target Genes of Aberrant ETS Transcription Factors Are Differentially Affected in Ewing’s Sarcoma and Prostate Carcinoma

“…These findings indicate that HIST1H4L is a potential target of ERG fusion genes, as also illustrated by our demonstration of direct binding of ERG to the HIST1H4L promoter, but the mechanism whereby it is involved in prostate carcinogenesis is still unknown. KCNN2 codes for a small conductance Ca 2+ - activated potassium channel involved in the regulation of the neuronal excitability [55], and, to our knowledge, we here show for the first time that this gene is overexpressed in PCa harboring ERG rearrangements when compared to the other subtypes of PCa and to NPT. On the other hand, KCNN2 was underexpressed in both PCa with other ETS rearrangements and in those without ETS rearrangements when compared to NPT.…”

Postnatal Expression of an Apamin-Sensitive K(Ca) Current in Vestibular Calyx Terminals

“…However, we found an effect of apamin on evoked single action potentials in calyces and further studies in more intact preparations, where connections to hair cells and ganglion are preserved, should elucidate the role of SK in discharge regularity in primary vestibular afferents. Interestingly BK null mutant mice have no obvious vestibular deficits (Pyott et al 2007), but an SK mutant shows locomotion problems that may be linked to disruption of vestibular processing (Szatanik et al 2008). Although deficits in this mutant may arise due to lack of functional central SK channels, which have been demonstrated in vestibular nucleus neurons (Dutia and Johnston 1998; Saito et al 2008; Smith et al 2002), our results suggest that SK channels in vestibular calyces may also play an important role in the peripheral processing of vestibular signals.…”

Animal models of human genetic diseases: do they need to be faithful to be useful?

“…However, over the last decade, familial cases have been reported indicating that the syndrome may also have a genetic component and a number of genes that definitively cause PD have been identified with recessive and dominant alleles. Several rat or mouse mutations have also been described that recapitulate some features of the disease and have been presented as potential animal models but none of them replicate the human syndrome with all its pathological aspects (Callizot et al 2001;Craig et al 2001;Szatanik et al 2008; for a review, see also Dawson et al 2010). In spite of this complex situation, scientists believe that it is important to continue developing mouse models for this complex disease provided they exhibit at least a key neuropathological or clinical feature of PD because, in the future, combinatorial study of these different models may provide insight into the pathogenesis of the disease.…”