Knockdown of the CXCL12/CXCR7 chemokine pathway results in learning deficits and neural progenitor maturation impairment in mice

Abstract

In adult brain, the chemokine CXCL12 and its receptors CXCR4 and CXCR7 are expressed in neural progenitor and glial cells. Conditional Cxcl12 or Cxcr4 gene knockout in mice leads to severe alterations in neural progenitor proliferation, migration and differentiation. As adult hippocampal neurogenesis is involved in learning and memory processes, we investigated the long-term effects of reduced expression of CXCL12 or CXCR7 in heterozygous Cxcl12+/− and Cxcr7+/− animals (KD mice) on hippocampal neurogenesis, neuronal differentiation and memory processing. In Cxcl12 KD mice, Cxcr4 mRNA expression was reduced, whereas Cxcr7 was slightly increased. Conversely, in Cxcr7 KD mice, both Cxcr4 and Cxcl12 mRNA levels were decreased. Moreover, Cxcl12 KD animals showed marked behavioral and learning deficits that were associated with impaired neurogenesis in the hippocampus. Conversely, Cxcr7 KD animals showed mild learning deficits with normal neurogenesis, but reduced cell differentiation, measured with doublecortin immunolabeling. These findings suggested that a single Cxcl12 or Cxcr7 allele might not be sufficient to maintain the hippocampal niche functionality throughout life, and that heterozygosity might represent a susceptibility factor for memory dysfunction progression.