Long-term perturbation of spine plasticity results in distinct impairments of cognitive function

Abstract

Dendritic spines serve as the post-synaptic structural component of synapses. The structure and function of dendritic spines are dynamically regulated by a number of signaling pathways and allow for normal neural processing, whereas aberrant spine changes are thought to contribute to cognitive impairment in neuropsychiatric and neurodegenerative disorders. However, spine changes within different brain regions and their contribution to specific cognitive functions, especially later in adulthood, is not well understood. In this study, we used late-adult KALRN-deficient mice as a tool to investigate the vulnerability of different cognitive functions to long-term perturbations in spine plasticity in different forebrain regions. We found that in these mice, loss of one or both copies of KALRN lead to genotype and brain region-dependent reductions in spine density. Surprisingly, heterozygote and knockout mice showed differential impairments in cognitive phenotypes, including working memory, social recognition, and social approach. Correlation analysis between the site and magnitude of spine loss and behavioral alterations suggests that the interplay between brain regions is critical for complex cognitive processing and underscores the importance of spine plasticity in normal cognitive function. Long-term perturbation of spine plasticity results in distinct impairments of cognitive function. Using genetically modified mice deficient in a central regulator of spine plasticity, we investigated the brain region-specific contribution of spine numbers to various cognitive functions. We found distinct cognitive functions display differential sensitivity to spine loss in the cortex and hippocampus. Our data support spines as neuronal structures important for cognition and suggest interplay between brain regions is critical for complex cognitive processing.

Fig. 1

Kalirin-deficient mice demonstrate differential synaptic deficits in the forebrain. (a, b) Golgi-impregnated pyramidal neurons from apical dendrites in the frontal cortex and CA1 region of the hippocampus in WT, HET and KO mice. (c) Quantification of spine density reveals substantial reductions in cortex of HET and KO mice (***, p < 0.0001). (d) Hippocampal spine density was only decreased in KO mice (*, comparison between WT and KO, p < 0.05; †, comparison between HET and KO, p < 0.05). Scale bars, 4μm. Data are represented as mean ± S.E.M.

Fig. 2

Impaired cognitive performance in kalirin-deficient mice. (a) Working memory in 11 – 14 month old kalirin-deficient mice assessed by performance on spontaneous alternation in the Y-maze. The KO mice were significantly impaired compared to WT, and HET mice displayed an intermediate phenotype but were still significantly impaired relative to WT (***, p < 0.0001; *, p < 0.05). Dashed line indicates chance level performance (50%). (b) Activity in the Y-maze, as measured by total number of arms entered, showed no difference between WT, HET and KO mice. Data presented as mean ± S.E.M.

Fig. 3

Altered social recognition and sociability in kalirin-deficient mice. (a) The difference in investigation between trials of a social recognition task was significantly reduced in KO mice compared to WT and HET mice (***, p < 0.0001). (b) The percent time spent investigating the juvenile mouse during trial 2 relative to trial 1 shows KO mice have reduced social recognition when compared to WT and HET mice (***, p < 0.0001), but all groups differed from 100 (#, p < 0.001). (c) KO mice spent less time investigating a novel juvenile mouse than did WT or HET mice (*, comparison between WT and KO, p < 0.05; †, comparison between HET and KO, p < 0.05). Data are represented as mean ± S.E.M.

Fig. 4

Kalirin-deficient mice display locomotor hyperactivity (a) Traces tracking the activity of WT, HET or KO mice during free exploration in an open field. The open field was divided into three zones (starting from the outermost): Outer, mid and inner. (b) Activity measurements in the open field demonstrating increased locomotor hyperactivity in KO mice when compared to WT and HET (**, p < 0.01), with WT and HET mice displaying similar activity levels. (c) Quantification of normalized time spent in each open field zone reveals no differences between WT, HET and KO mice. All mice spent the majority of their time in the outer zone, typical of mouse behavior, yielding a main effect for this open field zone [F(2, 108) = 100.00; p < 0.0001]. Data are represented as mean ± S.E.M.

Fig. 5

Correlations of spine density to behavioral phenotypes. (a) Working memory performance plotted against mean spine density in the frontal cortex of individual WT, HET and KO mice (r = 0.435, p > 0.05). Working memory was assessed by the spontaneous alternation task in the Y-maze, and reported as percent alternation. (b) Working memory performance plotted against an integrated spine density score (r = 0.361, p > 0.05). (c) Correlation between social recognition and mean hippocampal spine density from CA1 apical dendrites in WT, HET and KO mice (r = 0.298, p > 0.05). The difference in investigation time from trial 1 to trial 2 yielded the social recognition score, reported as investigation difference. (d) Correlation between social recognition and an integrated spine density score revealed a significant relationship (r = 0.682, p < 0.05). Pearson’s test was used to determine correlation for all data sets.