Dataset Information

Behavioral Abnormalities in Knockout and Humanized Tau Mice.

ABSTRACT: Microtubule-associated protein tau assists in stabilizing microtubules and has been particularly implicated in Alzheimer's disease (AD). Given the importance of tau to AD pathogenesis and therapies, it is important to understand non-classic physiological functions for this protein inside and outside the central nervous system (CNS). Our group has previously shown that tau ablation triggers glucose intolerance and pancreatic dysfunction in mice, suggesting that tau plays a role in peripheral metabolic regulation. Little is known about the role of tau in anxiety. Moreover, inconsistent results have been generated regarding the effects of tau deletion in memory. Here, we characterize systemic insulin resistance, anxiety-related behavior and memory in 15 to 20 weeks old Wild-Type (WT), Tau knockout (TauKO) and a distinct hTau mouse model consisting of tau knockout expressing the longest isoform (2N4R) of a non-mutant WT human Tau protein under the prion promoter (hTau). Our findings demonstrate that tau deletion leads to anxiety-related behavior, impaired contextual and cued fear memory. The presence of a human Tau transgene did not ameliorate the phenotypes observed in animals lacking the mouse tau protein and it elicited impairments in learning, memory, and peripheral insulin sensitivity. Our results suggest that tau protein plays a role in memory and anxiety-related behavior. Our findings also indicate that previously unrecognized functions for tau protein may be a complicating factor in using animal models on the TauKO background. Understanding the link between tau pathophysiology and cognitive and metabolic alterations is of great importance to establish the complete contribution of tau protein to AD pathogenesis.

SUBMITTER: Goncalves RA

PROVIDER: S-EPMC7080660 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Similar Datasets

Project description:Christianson syndrome (CS) is an X-linked neurodevelopmental and neurological disorder characterized in males by core symptoms that include non-verbal status, intellectual disability, epilepsy, truncal ataxia, postnatal microcephaly and hyperkinesis. CS is caused by mutations in the SLC9A6 gene, which encodes a multipass transmembrane sodium (potassium)-hydrogen exchanger 6 (NHE6) protein, functional in early recycling endosomes. The extent and variability of the CS phenotype in female heterozygotes, who presumably express the wild-type and mutant SLC9A6 alleles mosaically as a result of X-chromosome inactivation (XCI), have not yet been systematically characterized. Slc9a6 knockout mice (Slc9a6 KO) were generated by insertion of the bacterial lacZ/?-galactosidase (?-Gal) reporter into exon 6 of the X-linked gene. Mutant Slc9a6 KO male mice have been shown to develop late endosomal/lysosomal dysfunction associated with glycolipid accumulation in selected neuronal populations and patterned degeneration of Purkinje cells (PCs). In heterozygous female Slc9a6 KO mice, ?-Gal serves as a transcriptional/XCI reporter and thus facilitates testing of effects of mosaic expression of the mutant allele on penetrance of the abnormal phenotype. Using ?-Gal, we demonstrated mosaic expression of the mutant Slc9a6 allele and mosaically distributed lysosomal glycolipid accumulation and PC pathology in the brains of heterozygous Slc9a6 KO female mice. At the behavioral level, we showed that heterozygous female mice suffer from visuospatial memory and motor coordination deficits similar to but less severe than those observed in X-chromosome hemizygous mutant males. Our studies in heterozygous Slc9a6 KO female mice provide important clues for understanding the likely phenotypic range of Christianson syndrome among females heterozygous for SLC9A6 mutations and might improve diagnostic practice and genetic counseling by helping to characterize this presumably underappreciated patient/carrier group.

Project description:AimsSynaptic Ras GTPase-activating protein 1 (SYNGAP1) regulates synaptic plasticity through AMPA receptor trafficking. SYNGAP1 mutations have been found in human patients with intellectual disability (ID) and autism spectrum disorder (ASD). Almost every individual with SYNGAP1-related ID develops epilepsy, and approximately 50% have ASD. SYNGAP1-related ID is estimated to account for at least 1% of ID cases. In mouse models with Syngap1 mutations, strong cognitive and affective dysfunctions have been reported, yet some findings are inconsistent across studies. To further understand the behavioral significance of the SYNGAP1 gene, we assessed various domains of behavior in Syngap1 heterozygous mutant mice using a behavioral test battery.MethodsMale mice with a heterozygous mutation in the Syngap1 gene (Syngap1-/+ mice) created by Seth Grant's group were subjected to a battery of comprehensive behavioral tests, which examined general health, and neurological screens, rotarod, hot plate, open field, light/dark transition, elevated plus maze, social interaction, prepulse inhibition, Porsolt forced swim, tail suspension, gait analysis, T-maze, Y-maze, Barnes maze, contextual and cued fear conditioning, and home cage locomotor activity. To control for type I errors due to multiple-hypothesis testing, P-values below the false discovery rate calculated by the Benjamini-Hochberg method were considered as study-wide statistically significant.ResultsSyngap1-/+ mice showed increased locomotor activity, decreased prepulse inhibition, and impaired working and reference spatial memory, consistent with preceding studies. Impairment of context fear memory and increased startle reflex in Syngap1 mutant mice could not be reproduced. Significant decreases in sensitivity to painful stimuli and impaired motor function were observed in Syngap1-/+ mice. Decreased anxiety-like behavior and depression-like behavior were noted, although increased locomotor activity is a potential confounding factor of these phenotypes. Increased home cage locomotor activity indicated hyperlocomotor activity not only in specific behavioral test conditions but also in familiar environments.ConclusionIn Syngap1-/+ mice, we could reproduce most of the previously reported cognitive and emotional deficits. The decreased sensitivity to painful stimuli and impaired motor function that we found in Syngap1-/+ mice are consistent with the common characteristics of patients with SYNGAP-related ID. We further confirmed that the Syngap1 heterozygote mouse recapitulates the symptoms of ID and ASD patients.

Dataset Information

Behavioral Abnormalities in Knockout and Humanized Tau Mice.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets