Neuropilin and Tolloid‐Like 1 (Neto1) Deficiency Impairs, but CX614 Promotes Cognitive Flexibility

Abstract

Chromosome 18q‐ hemizygous deletions confer behavioral deficits that include cognitive inflexibility and social behavior impairments resembling autism. A candidate gene on 18q that may shape these behaviors is neuropilin (NRP) and tolloid (TLL)‐like 1 or NETO1. Neto1 may be a key regulator of glutamate transmission. It is an auxiliary subunit of kainate (KA), alpha‐amino‐3‐hydroxy‐5‐methylisoxazole‐4‐propionate (AMPA), and N‐methyl‐D‐aspartate (NMDA) receptors that is expressed mainly in hippocampus. Neto1 knockout mice exhibit cognitive deficits and disrupted long‐term potentiation that was corrected in previous studies by ampakines. To assess the impact of Neto1 deficiency on cognitive flexibility, water T‐maze tests were performed on adult female mice of all Neto1 genotypes. Mice were trained over 5 days to swim to the arm in the t‐maze with a raised platform, and then the position of the platform was switched to assess reversal‐learning capacity. Reversal learning in female mice remained unimpaired by the Neto1 deficiency, so we tested the response of male mice under similar conditions. A follow‐up study in male Neto1 heterozygotes with daily ampakine (CX614) injection showed that this treatment improved cognitive flexibility, but it also delayed initial platform location learning. To assess the impact of Neto1 on repetitive behavior, we performed marble burying tests on male Neto1 genotypes and found knock‐outs bury fewer marbles in bedding (4.6 ± 0.9) than wild‐type (9 ± 0.9). Neto1 deficient versus wild‐type social dominance was compared in a tube test, and while male mice were more dominant than females, there were no genotype differences. To compare the social behavior across Neto1 genotypes, we employed three‐chamber tests in which wild‐type mice (C57BL/6 strain) normally exhibit a significant preference (p < 0.05, N=8) for social interaction. Male Neto1 mice (8 – 11 weeks old) were tested for social interaction preference. The mice had 10 minutes to explore either a stranger (129S male age‐matched) under a cup cage or a novel object (empty cage). In male mice we found that all three Neto1 genotypes exhibited preference for social interaction, based on times engaged in social sniffing (F(1,33) =31.3, p < 0.05, N=10–14). In subsequent social novelty preference tests, Neto1 knock‐outs had reduced preference for social novelty relative to wild‐type or heterozygotes (F(1,33) = 7.35, p < 0.05, N=10–14). No significant differences in social interaction or social novelty preference were found among Neto1 genotypes. Glutamate receptors density was measured in the hippocampus by autoradiography and showed reduced [3H] KA binding in hippocampus of Neto1 deficient mice. Hence the greatest effect of Neto1 deficiency we observed was impairment of cognitive flexibility in male mice.Support or Funding InformationSupported by: Chromosome 18 Registry & Research Society, Voelcker Foundation and subawards from UL1‐TR001120 and GM097632This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.