Excessive activation of AhR signaling disrupts neuronal migration in the hippocampal CA1 region in the developing mouse

Abstract

-The aryl hydrocarbon receptor (AhR) avidly binds dioxin, a ubiquitous environmental contaminant. Disruption of downstream AhR signaling has been reported to alter neuronal development, and rodent offspring exposed to dioxin during gestation and lactation showed abnormalities in learning and memory, emotion, and social behavior. However, the mechanism behind the disrupted AhR signaling and developmental neurotoxicity induced by xenobiotic ligands remains elusive. Therefore, we studied how excessive AhR activation affects neuronal migration in the hippocampal CA1 region of the developing mouse brain. We transfected constitutively active (CA)-AhR, AhR, or control vector plasmids into neurons via in utero electroporation on gestational day 14 and analyzed neuronal positioning in the hippocampal CA1 region of offspring on postnatal day 14. CA-AhR transfection affected neuronal positioning, whereas no change was observed in AhR-transfected or control hippocampus. These results suggest that constitutively activated AhR signaling disrupts neuronal migration during hippocampal development. Further studies are needed to investigate whether such developmental disruption in the hippocampus leads to the abnormal cognition and behavior of rodent offspring upon maternal exposure to AhR xenobiotic ligands.

Does kynurenic acid act on nicotinic receptors? An assessment of the evidence

“…2 A summary of the major molecular targets known for kynurenic acid, with an indication of the qualitative and quantitative activity expanded in the text. The citation numbers refer to the following: [1] Henderson et al, 1990;[2] Watson et al 1988;[3] Kessler et al 1989a;[4] Kessler et al 1989b;[5] Kloog et al 1990;[6] Mayer et al 1988;[7] Olverman et al 1988;[8] Moroni et al 1989;[9] Robinson et al 1985; [10] Danysz et al 1989a;[11] Danysz et al 1989b;[12] Fisher and Mott, 2011;[13] DiNatale et al 2010;[14] Opitz et al 2011;[15] Kimura et al 2017;[16] Wang et al 2006;[17] Guo et al 2008;[18] Kubicova et al 2019;[19] Lugo-Huitron et al 2011. synaptic potentials ). The postsynaptic site of action of kynurenate was confirmed in a quantal analysis of synaptic transmission which revealed a decrease in the mean quantal size of excitatory potentials by kynurenate, but no change in the number of quanta released per stimulus (Brooks et al 1986), consistent with an action of kynurenate at postsynaptic targets.…”

The Aryl Hydrocarbon Receptor and the Nervous System

“…Migration processes of normal neuronal cells might also be disrupted by the receptor [ 90 ], as the use of constitutively activated AhR demonstrates that excessive AhR activity impairs neuronal migration in the hippocampus [ 91 ]. However, it is also important to mention that species-specific differences may also exist due to differences of AhR affinities or expression [ 92 ].…”

Impaired dendritic growth and positioning of cortical pyramidal neurons by activation of aryl hydrocarbon receptor signaling in the developing mouse

“…In the present study, CA-AhR transfection disrupted neuronal positioning in the cerebral cortex ( Fig 4 ). Because AhR-transfected hippocampal neurons were found not to alter neuronal positioning [ 56 ], it is feasible to speculate that neuronal positioning in the cerebral cortex could not be altered in the AhR group. In cortical projection neurons, “late-born” neurons migrate radially toward the brain surface and pass “early-born” neurons, which forces the early-born neurons to be aligned in the deeper layers, the phenomenon of which is expressed as an “inside-out” manner [ 57 ].…”