Progression of multiple behavioral deficits with various ages of onset in a murine model of Hurler syndrome

Abstract

Mucopolysaccharidosis type I (MPS I) is one of the most common lysosomal storage diseases with progressive neurological dysfunction. To characterize the chronological behavioral profiles and identify the onset of functional deficits in a MPS I mouse model (IDUA −/− ), we evaluated anxiety, locomotor behavior, startle, spatial learning and memory with mice at 2-, 4-, 6-and 8-months of age. In automated open-field test, IDUA −/− mice showed hypoactivity as early as 2-months of age and altered anxiety starting from 6-months of age during the initial exploratory phase, even through normal habituation was observed at all ages. In the marble-burying task, the anxiety-like compulsive behavior was normal in IDUA −/− mice at almost all tested ages, but significantly reduced in 8-month old male IDUA −/− mice which coincided with the rapid death of IDUA −/− males starting from 7-months of age. In the Morris water maze, IDUA −/− mice exhibited impaired proficient learning only at 4-months of age during the acquisition phase. Spatial memory deficits were observed in IDUA −/− mice during both 1-and 7-days probe trials at 4-and 8-months of age. The IDUA −/− mice performed normally in a novel object recognition task at younger ages until 8 month old when reduced visual cognitive memory retention was noted in the IDUA −/− mice. In addition, 8-month old IDUA −/− mice failed to habituate to repeated open-field exposure, suggesting deficits in nonaversive and non-associative memory. In acoustic startle assessment, significantly more non-responders were found in IDUA −/− , but normal performance was seen in those that did show a response. These results presented a temporal evaluation of phenotypic behavioral dysfunctions in IDUA −/− mice from adolescent to maturity, indicating the impairments, with different age of onset, in locomotor and anxiety-like compulsive behaviors, spatial learning and memory, visual recognition, and short-term non-associative memory retention. This study would also provide guidelines for the experimental designs of behavioral evaluation on innovative therapies for the treatment of MPS type I.

Lysosomal storage disease: Gene therapy on both sides of the blood–brain barrier

“…Therefore, functions evaluated in different studies may not be the same and tests with the same name may not examine the same parameters. Several behavioral tests used by some, do not show a difference between normal and affected mice in the experiments of others, as has been the case with a variant of the Morris Water Maze [113, 139, 140] and rotarod [113, 138] (and our unpublished observations). Some of the discrepancies may be due to a desire to present data that show positive therapeutic effects.…”

Normalization and Improvement of CNS Deficits in Mice With Hurler Syndrome After Long-term Peripheral Delivery of BBB-targeted Iduronidase

“…24 Mice were exposed to the same open-field for three repeated trials with a 30-minute intertrial interval (Figure 6). The difference between the first and third trials was determined for frequency of horizontal grid crossing and time spent on grooming.…”

“…The repeated open-field test was performed after bone marrow transplantation at the age of 7 months, as described previously. 24 The test was performed using an open-field test apparatus (60 × 60 cm) consisting of a white Plexiglas box with 25 squares (12 × 12 cm) painted on the floor (16 outer and 9 inner). Mice were placed in one of the four corners of the apparatus and allowed to explore the whole field freely for 5 minutes.…”

Reprogramming erythroid cells for lysosomal enzyme production leads to visceral and CNS cross-correction in mice with Hurler syndrome

“…5A). This test has been shown previously to characterize nonaversive and nonassociative memory deficits in MPS I mice without gender differences (23). Mice were exposed to the same open field for 3 repeated trials, with 30-min intertrial intervals.…”