Vangl2, a Core Component of the WNT/PCP Pathway, Regulates Adult Hippocampal Neurogenesis and Age-Related Decline in Cognitive Flexibility

Abstract

Decline in episodic memory is one of the hallmarks of aging and represents one of the most important health problems facing Western societies. A key structure in episodic memory is the hippocampal formation and the dentate gyrus in particular, as the continuous production of new dentate granule neurons in this brain region was found to play a crucial role in memory and age-related decline in memory. As such, understanding the molecular processes that regulate the relationship between adult neurogenesis and aging of memory function holds great therapeutic potential. Recently, we found that Vang-Gogh like 2 (Vangl2), a core component of the Planar Cell Polarity (PCP) signaling pathway, is enriched in the dentate gyrus of adult mice. In this context, we sought to evaluate the involvement of this member of the Wnt/PCP pathway in both adult neurogenesis and memory abilities in adult and middle-aged mice. Using a heterozygous mouse model carrying a dominant-negative mutation in the Vangl2 gene, called Looptail (Vangl2Lp), we show that alteration in Vangl2 expression decreases the survival of adult-born granule cells and advances the onset of a decrease in cognitive flexibility. The inability of mutant mice to erase old irrelevant information to the benefit of new relevant ones highlights a key role of Vangl2 in interference-based forgetting. Taken together, our findings show that Vangl2 activity may constitute an interesting target to prevent age-related decline in hippocampal plasticity and memory.

Age-related decline in cognitive flexibility is associated with the levels of hippocampal neurogenesis

“…Another hallmark of aging is the decrease in production of new neurons in the dentate gyrus (DG) of the hippocampus, a brain region that supports neurogenesis in humans and animals long after birth ( Kuhn et al, 1996 ; Encinas et al, 2011 ; Boldrini et al, 2018 ; Kempermann et al, 2018 ; Pilz et al, 2018 ; Shetty et al, 2018 ; Sorrells et al, 2018 ; Lazutkin et al, 2019 ; Tobin et al, 2019 ; Toda et al, 2019 ; Urban et al, 2019 ; Bottes et al, 2021 ; Ibrayeva et al, 2021 ; Wu et al, 2023 ). Adult-born hippocampal neurons are believed to play diverse roles, including their involvement in distinguishing subtle differences in familiar contexts (pattern separation), supporting behavioral flexibility, and promoting active forgetting ( Saxe et al, 2006 ; Clelland et al, 2009 ; Arruda-Carvalho et al, 2011 ; Sahay et al, 2011b ; Burghardt et al, 2012 ; Niibori et al, 2012 ; Tronel et al, 2012 ; Aimone et al, 2014 ; Akers et al, 2014 ; Epp et al, 2016 ; McAvoy et al, 2016 ; Anacker and Hen, 2017 ; Toda et al, 2019 ; Yu et al, 2019 ; Lods et al, 2021 ; Koehl et al, 2022 ). A growing body of evidence indicates that decreased hippocampal neurogenesis is associated with impaired performance in a variety of learning and memory tasks [e.g., MWM and contextual fear conditioning ( Hernandez-Mercado and Zepeda, 2021 )]; moreover, experimental enhancement of neurogenesis has been shown to improve performance in relevant cognitive tests ( Sahay et al, 2011a ; McAvoy and Sahay, 2017 ; Berdugo-Vega et al, 2020 ; Montaron et al, 2020 ).…”