Hippocampal dysfunction in the Euchromatin histone methyltransferase 1 heterozygous knockout mouse model for Kleefstra syndrome

Abstract

Euchromatin histone methyltransferase 1 (EHMT1) is a highly conserved protein that catalyzes mono- and dimethylation of histone H3 lysine 9, thereby epigenetically regulating transcription. Kleefstra syndrome (KS), is caused by haploinsufficiency of the EHMT1 gene, and is an example of an emerging group of intellectual disability (ID) disorders caused by genes encoding epigenetic regulators of neuronal gene activity. Little is known about the mechanisms underlying this disorder, prompting us to study the Euchromatin histone methyltransferase 1 heterozygous knockout (Ehmt1(+/-)) mice as a model for KS. In agreement with the cognitive disturbances observed in patients with KS, we detected deficits in fear extinction learning and both novel and spatial object recognition in Ehmt1(+/-) mice. These learning and memory deficits were associated with a significant reduction in dendritic arborization and the number of mature spines in hippocampal CA1 pyramidal neurons of Ehmt1(+/-) mice. In-depth analysis of the electrophysiological properties of CA3-CA1 synapses revealed no differences in basal synaptic transmission or theta-burst induced long-term potentiation (LTP). However, paired-pulse facilitation (PPF) was significantly increased in Ehmt1(+/-) neurons, pointing to a potential deficiency in presynaptic neurotransmitter release. Accordingly, a reduction in the frequency of miniature excitatory post-synaptic currents (mEPSCs) was observed in Ehmt1(+/-) neurons. These data demonstrate that Ehmt1 haploinsufficiency in mice leads to learning deficits and synaptic dysfunction, providing a possible mechanism for the ID phenotype in patients with KS.

Deep brain stimulation for the obsessive-compulsive and Tourette-like symptoms of Kleefstra syndrome

“…The presence of OCD and TS symptoms in a monogenetic disease such as Kleefstra syndrome offers an intriguing avenue for the study of both disease and treatment through the exploration of animal models. Initial studies in EHMT1 knockout mice have demonstrated some behavioral abnormalities proposed to be consistent with the intellectual disability, autistic features, and anxiety seen in Kleefstra syndrome, 1,2 and further study of these models will, we hope, provide additional insight. The decline in function following electrode malfunction and subsequent recovery following reimplantation implicates DBS as the likely causal factor for the patient's improvement.…”

Histone Methylation by the Kleefstra Syndrome Protein EHMT1 Mediates Homeostatic Synaptic Scaling

“…This suggests that synaptic scaling plays a critical role in experience-dependent development. We evaluated H3K9me2 fluorescence and mEPSCs in V1 after 3 days of light deprivation (dark-reared [DR]), comparing WT to Ehmt1 +/À mice, since the Ehmt1 +/À mouse recapitulates core features of Kleefstra syndrome (Balemans et al, 2010(Balemans et al, , 2013(Balemans et al, , 2014. H3K9me2 fluorescence was significantly higher in NeuN-positive V1 layer II/III cells of WT DR mice ( Figures 6A and 6B).…”

“…Interestingly, H3K9me2 is an epigenetic mark that is dynamically regulated in the hippocampus and nucleus accumbens during contextual fear memory formation, addiction, and stress (Boulle et al, 2014;Chase and Sharma, 2013;Covington et al, 2011;Gupta et al, 2010;Gupta-Agarwal et al, 2012Heller et al, 2014;Maze et al, 2010). Genetic and pharmacological manipulations of EHMT1/2 in vivo have also shown that EHMT signaling is important for long-term memory formation both in mouse and Drosophila (Balemans et al, 2013;Gupta-Agarwal et al, 2012;Kramer et al, 2011;Schaefer et al, 2009).…”

Histone H3 lysine methylation in cognition and intellectual disability disorders

“…The protein complex between EHMT1 and EHMT2 (aka G9a or KMT1C) participates in the maintenance of heterochromatin and its deficiency leads to derepression of nonneuronal genes in adult neurons and defects in learning, motivation, and environmental adaptation (Schaefer et al 2009). Thus, EHMT1 heterozygous mice (Ehmt1 +/2 ) exhibit behavioral deficits, such as hypoactivity, reduced exploration, increased anxiety, and aberrant social behavior (Balemans et al 2010), and express deficits in fear extinction learning and novel and spatial object recognition memory, aberrant dendritic arborization in CA1 pyramidal neurons, and decreased basal synaptic transmission and long-term potentiation (Balemans et al 2013). These defects are reminiscent of the autistic features, hypoactivity, and cognitive abnormalities reported in patients with Kleefstra syndrome (Kleefstra et al 2010).…”