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.