Impact of DNMT1 and DNMT3a forebrain knockout on depressive- and anxiety like behavior in mice

Abstract

DNA methylation has been shown to impact certain forms of synaptic and behavioral plasticity that have been implicated in the development in psychiatric disorders. DNA methylation is catalyzed by DNA methyltransferase (DNMT) enzymes that continue to be expressed in postmitotic neurons in the forebrain. Using a conditional forebrain knockout of DNMT1 or DNMT3a we assessed the role of these DNMTs in anxiety and depressive-like behavior in mice using an array of behavioral testing paradigms. Forebrain deletion of DNMT1 had anxiolytic and antidepressant-like properties as assessed by elevated plus maze, novelty suppressed feeding, forced swim, and social interaction tests. DNMT3a knockout mice, by contrast, did not exhibit significant behavioral alterations in these tests. Given the putative role of altered DNA methylation patterns in the development of schizophrenia, we also assessed DNMT1 and DNMT3a knockout mice in a prepulse inhibition task and found an enhanced prepulse inhibition of startle in DNMT1 knockouts relative to wild type mice, with no change evident in DNMT3a knockout mice. Our data suggest that DNMT1 and DNMT3a are distinctly involved in affective behavior and that DNMT1 may ultimately represent a potential target for treatment of certain affective behavioral disorders.

Exposure to extrinsic stressors, social defeat or bisphenol A, eliminates sex differences in DNA methyltransferase expression in the amygdala

“…When a conditional knockout mouse was used to inactivate Dnmt1 in the forebrain (including amygdala) 2‐3 weeks after birth, synaptic plasticity in the hippocampus and spatial memory were impaired . Male conditional Dnmt1 knockout mice also had reduced anxiety‐like behaviour in the open field and increased social interaction behaviour . The loss of Dnmt1 may have broad effects on transcription that could contribute to increases in anxiety‐like behaviour.…”

“…40 Male conditional Dnmt1 knockout mice also had reduced anxiety-like behaviour in the open field and increased social interaction behaviour. 41 The loss of Dnmt1 may have broad effects on transcription that could contribute to increases in anxiety-like behaviour. The results of the present study suggest that Dnmt1 inhibition may have even more robust effects in females.…”

Hypothesis: Regulation of neuroplasticity may involve I-motif and G-quadruplex DNA formation modulated by epigenetic mechanisms

“…DNMT3A appears to be the specific subtype required for normal de novo learning and memory. Forebrain specific DNMT3A knockout mice, but not DNMT1 knockout mice, had altered LTP and synaptic plasticity in the affected areas and showed learning and memory deficits 42 .…”

Envolvimento do óxido nítrico na metilação do DNA induzida por estresse

“…Esses efeitos foram acompanhados pela diminuição da metilação global do DNA e um aumento dos níveis de BDNF no hipocampo (Sales et al, 2011), sugerindo que o estresse promova aumento da metilação do gene para BDNF, reduzindo sua expressão, e assim levando a comportamento do tipo-depressivo em modelos animais. Corroborando essas informações animais knockout para a enzima DNMT1 apresentaram um fenótipo tipo antidepressivo avaliado no teste do nado forçado (Morris et al, 2016).…”

“…(Aid et al, 2007;Sales et al, 2011). Além disso, a inibição farmacológica da atividade das DNMTs ou a deleção gênica da expressão da enzima DNMT1, induz um efeito tipo antidepressivo em roedores submetidos ao estresse (Sales et al, 2011;Morris et al, 2016) (Sharma et al, 2013). Ademais, nesse mesmo estudo, foi descrito que o tratamento com dexametasona induz a formação de outros complexos proteicos, como GR-HDAC1-MeCP2, auxiliando a metilação do DNA na região promotora do gene do crh (Sharma et al, 2013).…”