The intellectual disability PAK3 R67C mutation impacts cognitive functions and adult hippocampal neurogenesis

Abstract

<jats:title>Abstract</jats:title> <jats:p>The link between mutations associated with intellectual disability (ID) and the mechanisms underlying cognitive dysfunctions remains largely unknown. Here, we focused on PAK3, a serine/threonine kinase whose gene mutations cause X-linked ID. We generated a new mutant mouse model bearing the missense R67C mutation of the Pak3 gene (Pak3-R67C), known to cause moderate to severe ID in humans without other clinical signs and investigated hippocampal-dependent memory and adult hippocampal neurogenesis. Adult male Pak3-R67C mice exhibited selective impairments in long-term spatial memory and pattern separation function, suggestive of altered hippocampal neurogenesis. A delayed non-matching to place paradigm testing memory flexibility and proactive interference, reported here as being adult neurogenesis-dependent, revealed a hypersensitivity to high interference in Pak3-R67C mice. Analyzing adult hippocampal neurogenesis in Pak3-R67C mice reveals no alteration in the first steps of adult neurogenesis, but an accelerated death of a population of adult-born neurons during the critical period of 18–28 days after their birth. We then investigated the recruitment of hippocampal adult-born neurons after spatial memory recall. Post-recall activation of mature dentate granule cells in Pak3-R67C mice was unaffected, but a complete failure of activation of young DCX + newborn neurons was found, suggesting they were not recruited during the memory task. Decreased expression of the KCC2b chloride cotransporter and altered dendritic development indicate that young adult-born neurons are not fully functional in Pak3-R67C mice. We suggest that these defects in the dynamics and learning-associated recruitment of newborn hippocampal neurons may contribute to the selective cognitive deficits observed in this mouse model of ID.</jats:p>

Disruption of PAK3 Signaling in Social Interaction Induced cFos Positive Cells Impairs Social Recognition Memory

“…In addition, we did not observe a deficit in spatial or fear memory acquisition or recall as evidenced by our Morris Water Maze and fear conditioning results. Our spatial memory test supports the results of a recent study that demonstrated that mPAK3 protein selectively impaired strained, massed spatial memory training protocols but not distributed spatial training such as our training protocol [15]. On the other hand, fear memory acquisition and retrieval may also be compensated by alternative pathways due to its evolutionary importance for survival [50].…”

“…Genetic studies have shown that various gene mutations of PAK3 cause moderate to severe ID with abnormal dendritic development and synapse formation without affecting the gross brain development in human patients [ 9 , 10 , 11 ]. In addition, mouse models generated based on the manipulations of PAK3 and its close family members display impaired synaptic function, including spine morphology and synaptic plasticity, as well as cognitive deficits, without alterations in the gross anatomy of the brain, as seen in human patients [ 12 , 13 , 14 , 15 , 16 , 17 ]. Therefore, these animal models provide powerful tools for specifically investigating the molecular processes underlying cognitive deficits.…”

“…PAK3 can form homodimers or heterodimers with its close family member, PAK1, and therefore affects overall PAK signaling processes [ 25 ]. Previous in vitro and in vivo studies have indicated that PAK3 regulates spine morphogenesis, long-term potentiation (LTP), and spatial memory through the regulation of actin reorganization and gene expression [ 13 , 15 , 16 , 26 , 27 , 28 ]. Particularly, a recent study has revealed that PAK3 is important for social recognition memory in mice [ 17 ].…”

KANPHOS: A Database of Kinase-Associated Neural Protein Phosphorylation in the Brain

“…Protein kinases such as Pak3, Limk1, ERK, and RSK2 have been implicated in intellectual disability [ 56 , 57 ]. However, the mechanisms by which these protein kinases are involved in intellectual disability are largely unknown.…”

Neuronal Cytoskeleton in Intellectual Disability: From Systems Biology and Modeling to Therapeutic Opportunities

“…In mice, the latter variant impacts cognitive functions and adult hippocampal neurogenesis [ 126 ]. Likewise, Pak3 -KO mice have no apparent defects in the actin cytoskeleton, but showed impaired hippocampal LTP, together with learning and memory deficits [ 127 ].…”