Haploinsufficiency of EHMT1 improves pattern separation and increases hippocampal cell proliferation

Abstract

Heterozygous mutations or deletions of the human Euchromatin Histone Methyltransferase 1 (EHMT1) gene are the main causes of Kleefstra syndrome, a neurodevelopmental disorder that is characterized by impaired memory, autistic features and mostly severe intellectual disability. Previously, Ehmt1+/− heterozygous knockout mice were found to exhibit cranial abnormalities and decreased sociability, phenotypes similar to those observed in Kleefstra syndrome patients. In addition, Ehmt1+/− knockout mice were impaired at fear extinction and novel- and spatial object recognition. In this study, Ehmt1+/− and wild-type mice were tested on several cognitive tests in a touchscreen-equipped operant chamber to further investigate the nature of learning and memory changes. Performance of Ehmt1+/− mice in the Visual Discrimination & Reversal learning, object-location Paired-Associates learning- and Extinction learning tasks was found to be unimpaired. Remarkably, Ehmt1+/− mice showed enhanced performance on the Location Discrimination test of pattern separation. In line with improved Location Discrimination ability, an increase in BrdU-labelled cells in the subgranular zone of the dentate gyrus was observed. In conclusion, reduced levels of EHMT1 protein in Ehmt1+/− mice does not result in general learning deficits in a touchscreen-based battery, but leads to increased adult cell proliferation in the hippocampus and enhanced pattern separation ability.

Multi-domain cognitive assessment of male mice reveals whole body exposure to space radiation is not detrimental to high-level cognition and actually improves pattern separation

“…However, we find pattern separation is improved in 56 Fe relative to Sham mice without a change in VMCL habit learning, suggesting normal dorsal striatal function. Finally, the improved pattern separation reported here is reminiscent of the excessive attention seen in some psychiatric disorders -such as autism or obsessive compulsive disorder (OCD) -and in animal models for these disorders (63,(106)(107)(108) . Evaluation of autistic-or OCD-like behavioral patterns after HZE particle exposure using other touchscreen paradigms (i.e.…”

“…To address these major knowledge gaps, mature C57BL/6J male mice received either Sham irradiation (IRR) or whole body 56 Fe particle IRR and were assessed on a battery of touchscreen cognitive tasks (54,56,(62)(63)(64)(65) .…”

The Object Space Task reveals a dissociation between semantic-like and episodic-like memory in a mouse model of Kleefstra Syndrome

“…Notably, other experiments also showed comparable performance between Ehmt1 +/and WT in some behavioral tasks that typically involve the cortex as well as the hippocampus, including spatial learning in the Barnes Maze 15 . Additionally, pattern separation learning in a touch-screen task is superior in Ehmt1 +/mice 16 . It is highly likely that successful extraction of statistical regularities in the overlapping condition of the Object Space task requires both the hippocampus and the neocortex 3,21,22 In sum, the dissociation between a deficit in episodic-like and intact semantic-like memory, may hint at a selective hippocampal and not cortical dysfunction in the Ehmt1 +/mouse model.…”

“…Ehmt1 +/mice perform similar to their wildtype controls in the Barnes-maze, a task that uses anxiety to the open field as a motivator, but show a deficit in simple object recognition or placement memory 15 . Interestingly, Ehmt1 +/mice outperform wildtypes in a touch-screen pattern separation task, a process that heavily depends on the dentate gyrus in the hippocampus 16 . Similar results on pattern separation have been demonstrated in human individuals with high-functioning autism 17 .…”

Distinct pathogenic genes causing intellectual disability and autism exhibit overlapping effects on neuronal network development

“…EHMT1 cooperates with its mammalian paralogue EHMT2/G9a and exhibits enzymatic activity for histone 3 lysine 9 mono-and di-methylation (H3K9me1 and H3K9me2, respectively), which is known to promote a heterochromatic structure and hence gene repression (18,19). Loss of EHMT1 function in mice and Drosophila leads to learning and memory impairments (20)(21)(22)(23)(24). Additionally, Ehmt1 +/mice recapitulate autistic-like features that are seen in patients with Kleefstra syndrome (20).…”