AhR Deletion Promotes Aberrant Morphogenesis and Synaptic Activity of Adult-Generated Granule Neurons and Impairs Hippocampus-Dependent Memory

Abstract Newborn granule cells are continuously produced in the subgranular zone of dentate gyrus throughout life. Once these cells mature, they integrate into pre-existing circuits modulating hippocampus-dependent memory. Subsequently, mechanisms controlling generation and maturation of newborn cells are essential for proper hippocampal function. Therefore, we have studied the role of Aryl Hydrocarbon Receptor (AhR), a ligand-activated bHLH-PAS transcription factor, in hippocampus-dependent memory and granule neuronal morphology and function using genetic loss-of-function approaches based on constitutive and inducible-nestin AhR -/- mice. The results presented here show that the impaired hippocampus-dependent memory in AhR absence is not due to its effects on neurogenesis but to aberrant dendritic arborisation and to an increased spine density albeit with a lower number of mature mushrooms spines in newborn granule cells, a finding that is associated to an immature electrophysiological phenotype. Together, our data strongly suggest that AhR plays a pivotal role in the regulation of hippocampal function, by controlling hippocampal granule neuron morphology and synaptic maturation. Significance Statement Hippocampus-dependent memory depends on the generation and maturation of dentate gyrus (DG) newborn granule cells. Aryl Hydrocarbon Receptor (AhR) is a ligand-activated bHLH-PAS transcription factor recently implicated in dendrite branching in the CNS. Since its role in the modulation of dendrite branching and plasticity of adult hippocampal newborn granule neurons and subsequent impact on hippocampus-dependent memory remains unknown, we have undertaken its study using genetic loss-of-function approaches in adult mice. Our study provides evidence indicating that AhR is a regulator of dendrite arborisation and proper synaptic maturation of adult hippocampal newborn neurons and showing its critical role for learning and memory function. These findings point out AhR as a new potent druggable target for the treatment of several cognitive disorders.