Dataset Information

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.

SUBMITTER: Benevento M

PROVIDER: S-EPMC5223204 | biostudies-literature | 2017 Jan

REPOSITORIES: biostudies-literature

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Haploinsufficiency of EHMT1 improves pattern separation and increases hippocampal cell proliferation.

Benevento Marco M Oomen Charlotte A CA Horner Alexa E AE Amiri Houshang H Jacobs Tessa T Pauwels Charlotte C Frega Monica M Kleefstra Tjitske T Kopanitsa Maksym V MV Grant Seth G N SG Bussey Timothy J TJ Saksida Lisa M LM Van der Zee Catharina E E M CE van Bokhoven Hans H Glennon Jeffrey C JC Kasri Nael Nadif NN

Scientific reports 20170110

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<sup>+/-</sup> heterozygous knockout mice were found to exhibit cranial abnormalities and decreased sociability, phenotypes similar to those observed in Kleefstra syndrome patients. In addition, Ehmt1<sup> ...[more]

PMID: 28071689

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Project description:Adult hippocampal neurogenesis is a unique form of neural circuit plasticity that results in the generation of new neurons in the dentate gyrus throughout life. Neurons that arise in adults (adult-born neurons) show heightened synaptic plasticity during their maturation and can account for up to ten per cent of the entire granule cell population. Moreover, levels of adult hippocampal neurogenesis are increased by interventions that are associated with beneficial effects on cognition and mood, such as learning, environmental enrichment, exercise and chronic treatment with antidepressants. Together, these properties of adult neurogenesis indicate that this process could be harnessed to improve hippocampal functions. However, despite a substantial number of studies demonstrating that adult-born neurons are necessary for mediating specific cognitive functions, as well as some of the behavioural effects of antidepressants, it is unknown whether an increase in adult hippocampal neurogenesis is sufficient to improve cognition and mood. Here we show that inducible genetic expansion of the population of adult-born neurons through enhancing their survival improves performance in a specific cognitive task in which two similar contexts need to be distinguished. Mice with increased adult hippocampal neurogenesis show normal object recognition, spatial learning, contextual fear conditioning and extinction learning but are more efficient in differentiating between overlapping contextual representations, which is indicative of enhanced pattern separation. Furthermore, stimulation of adult hippocampal neurogenesis, when combined with an intervention such as voluntary exercise, produces a robust increase in exploratory behaviour. However, increasing adult hippocampal neurogenesis alone does not produce a behavioural response like that induced by anxiolytic agents or antidepressants. Together, our findings suggest that strategies that are designed to increase adult hippocampal neurogenesis specifically, by targeting the cell death of adult-born neurons or by other mechanisms, may have therapeutic potential for reversing impairments in pattern separation and dentate gyrus dysfunction such as those seen during normal ageing.

Project description:Pattern separation is a central concept in current theories of episodic memory: this computation is thought to support our ability to avoid confusion between similar memories by transforming similar cortical input patterns of neural activity into dissimilar output patterns before their long-term storage in the hippocampus. Because there are many ways one can define patterns of neuronal activity and the similarity between them, pattern separation could in theory be achieved through multiple coding strategies. Using our recently developed assay that evaluates pattern separation in isolated tissue by controlling and recording the input and output spike trains of single hippocampal neurons, we explored neural codes through which pattern separation is performed by systematic testing of different similarity metrics and various time resolutions. We discovered that granule cells, the projection neurons of the dentate gyrus, can exhibit both pattern separation and its opposite computation, pattern convergence, depending on the neural code considered and the statistical structure of the input patterns. Pattern separation is favored when inputs are highly similar, and is achieved through spike time reorganization at short time scales (< 100 ms) as well as through variations in firing rate and burstiness at longer time scales. These multiplexed forms of pattern separation are network phenomena, notably controlled by GABAergic inhibition, that involve many celltypes with input-output transformations that participate in pattern separation to different extents and with complementary neural codes: a rate code for dentate fast-spiking interneurons, a burstiness code for hilar mossy cells and a synchrony code at long time scales for CA3 pyramidal cells. Therefore, the isolated hippocampal circuit itself is capable of performing temporal pattern separation using multiplexed coding strategies that might be essential to optimally disambiguate multimodal mnemonic representations.

Dataset Information

Haploinsufficiency of EHMT1 improves pattern separation and increases hippocampal cell proliferation.

Publications

Haploinsufficiency of EHMT1 improves pattern separation and increases hippocampal cell proliferation.

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