Altered neocortical cell density and layer thickness in serotonin transporter knockout mice: A quantitation study

The neurotransmitter serotonin (5-HT) plays morphogenetic roles during development, and their alteration could contribute to autism pathogenesis in humans. To further characterize 5-HT contributions to neocortical development, we assessed the thickness and neuronal cell density of various cerebral cortical areas in 5-HT transporter (5-HTT) knockout (ko) mice, characterized by elevated extracellular 5-HT levels. The thickness of layer IV is decreased in 5-HTT knockout mice compared to wildtype mice. The overall effect on cortical thickness, however, depends on the genetic background of the mice. Overall cortical thickness is decreased in many cortical areas of 5-HTT ko mice with a mixed c129-CD1-C57BL/6J background. Instead, 5-HTT ko mice backcrossed into the C57BL/6J background display increases in supragranular and infragranular layers, which compensate entirely for decreased layer IV thickness, resulting in unchanged, or even enhanced cortical thickness. Moreover, significant increases in neuronal cell density are found in 5-HTT ko mice with a C57BL/6J background (wt:hz:ko ratio = 1.00:1.04:1.17), but not in mixed c129-CD1-C57BL/6J 5-HTT ko animals. These results provide evidence of 5-HTT gene effects on neocortical morphology in epistatic interaction with genetic variants at other loci, and may model the effect of functional 5-HTT gene variants on neocortical development in autism.