A CAG repeat polymorphism of KCNN3 predicts SK3 channel function and cognitive performance in schizophrenia.
Long repeats reduce SK3 channel function, as we demonstrate by patch-clamping of transfected HEK293 cells.In contrast, modelling the opposite in mice, i.e. KCNN3 overexpression/channel hyperfunction, leads to selective deficits in higher brain functions comparable to those influenced by SK3 conductance in humans.Reduction of SK3 function may constitute a pharmacological target to improve cognition in schizophrenia and other conditions with cognitive impairment.
Affiliation: Divison of Clinical Neuroscience, Max Planck Institute of Experimental Medicine, Göttingen, Germany.
- Small-Conductance Calcium-Activated Potassium Channels/genetics*/metabolism
- Trinucleotide Repeats/genetics*
- Aged, 80 and over
- Base Sequence
- Case-Control Studies
- Cell Line
- Gene Frequency
- Middle Aged
- Patch-Clamp Techniques
- Polymorphism, Genetic
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fig02: SK3 overexpressing (T/T) mice show selective deficits in higher cognitionA,B. Comparative distribution of SK3 immunoreactivity in hippocampus (sagittal section) is presented for wildtype (A) versus SK3 T/T mice (B). Insets show magnifications of stained granule neurons in dentate gyrus and pyramidal neurons in Ammon's horn (CA2).C. Densitometrical quantification of SK3 protein expression in hippocampus and heart of WT and SK3 T/T mice (n = 6–7; **Student's t-test, t1,12 = 3.724, p = 0.0029; ***Student's t-test, t1,11 = 4.902, p = 0.0005). SK3 expression is presented as % of ß-actin (ß-Act) and normalized to the WT. Sample Western blots are shown below the bar chart. For quantification, the 74 kDa band was used for WT (endogeneous SK3) and the 70 kDa band for T/T (transgenic SK3 expression).D. WT and T/T behaviour is unaltered in elevated plus maze. Presented is the percentage of time spent in open arms against the total time spent in both open and closed arms.E-G. No differences in open field are observed between genotypes regarding time spent in different zones (E) or velocity (F). The latency to reach the wall after initial start from the centre of the open field (G) is significantly higher in SK3 T/T mice compared to WT (*Student's t-test, t1,26 = 2.318, p = 0.029).H. In hole board, SK3 T/T mice show significantly less exploratory activity than WT (***Student's t-test, t1,26 = 4.110, p = 0.0004).I. The two genotypes do not differ in motor performance/motor learning on rota-rod.J. SK3 T/T mice demonstrate longer escape latency in the hidden platform task (*two-way repeated measures ANOVA, F1,26 = 5.43, p = 0.028); in the probe trial (inset), SK3 T/T mice display absence of preference for the target quadrant (*Student's t-test, t1,26 = 2.250, p = 0.033).K. In contextual and cue memory test of fear conditioning, SK3 T/T mice freeze less (*Student's t-test, t1,26 = 2.212, p = 0.036, ***Student's t-test, t1,26 = 3.779, p = 0.0008). For all behavioural experiments: n = 13–15; data presented as mean ± s.e.m.; two-sided Student's t-tests used; * indicates p < 0.05, **p < 0.01 and ***p < 0.001.
Based on above findings and earlier data indicating that SK3 negatively regulates cognition (Blank et al, 2003), we hypothesized that a long CAG repeat length would result in a less functional SK3 channel and better cognition, while a short repeat length would lead to more efficient SK3 function and worse cognitive performance. To test this hypothesis, we analysed basic behaviour and cognition in a transgenic mouse line in which the murine SK3 gene is overexpressed under control of its own regulatory elements, enhanced in cis by the tetracyclin-dependent transactivator (tTA) in the absence of any doxycyclin (Bond et al, 2000). This SK3 overexpressing allele is referred to as SK3-T in the following. The overexpression of SK3 in this model is illustrated in Fig 2A and B, comparing hippocampal SK3 immunoreactivity in a wildtype (WT) and a SK3 T/T mouse. Densitometric analysis of the SK3 specific bands obtained by Western blot demonstrates the pronounced increase in SK3 protein in hippocampus (p = 0.0029) and heart (used as a control tissue; p = 0.0005) of SK3 T/T mice (Fig 2C).