Maged1 Co-interacting with CREB Through a Hexapeptide Repeat Domain Regulates Learning and Memory in Mice

Abstract

Maged1 is a member of the type II melanoma antigen (MAGE) family of proteins, which is highly conserved in the brain between mouse and human. Recently, Maged1 has been reported to be involved in depression and impaired sexual behavior. However, the role of Maged1 in learning and memory remains unknown. The aim of the present study was therefore to investigate whether Maged1 deficiency can impair learning and memory formation. By behavioral tests and electrophysiological recording, we observed that 5-6-month-old Maged1 knockout mice displayed the reduced basal synaptic transmission, pronounced hippocampal dysfunction, impaired spatial learning, and a deficit in long-term potentiation induction. Data from immunohistochemical and Western blot showed the reduced dendritic spine density and the number of synapses in the hippocampus of the Maged1 knockout mice, and Maged1 deficiency prevented the interaction of Maged1 with cAMP response element-binding protein (CREB). Furthermore, by chromatin immunoprecipitation and luciferase assay, we observed the downregulated activity of CREB and the suppressed CREB-dependent transcription after deficiency of Maged1, which lead to the decreased levels of brain-derived neurotrophic factor. Taken together, our results provide the evidence that Maged1 is involved in synaptic transmission and hippocampus-dependent learning and memory formation.

Xp11.22 deletions encompassing CENPVL1, CENPVL2, MAGED1 and GSPT2 as a cause of syndromic X-linked intellectual disability

“…Subsequently, Yang et al used behavioral tests and electrophysiological recording to show that 5–6-month-old Maged1 -null mice displayed reduced basal synaptic transmission, pronounced hippocampal dysfunction, impaired spatial learning, and a deficit in long-term potentiation induction [52]. They also showed that loss of MAGED1 resulted in a reduced dendritic spine density and a reduction in the number of synapses in the hippocampi of Maged1 -null mice.…”

Deletion of Maged1 in mice abolishes locomotor and reinforcing effects of cocaine

“…In this study, the promoter of Maged1 was found in the fourth position in a list of 213 promoters that co-precipitate with polyacetylated histones and with the activated form of cAMP response element binding protein (CREB), a transcription factor activated by cocaine and critical for behavioural responses to drugs of abuse [20]. Interestingly, Maged1 binds directly to CREB in the hippocampus [16]. In addition, Maged1 has been showed to interact with various partner proteins.…”

“…Here, we assessed the role of Maged1 in electrophysiological and behavioural correlates of addiction. Recent studies have shown that Maged1 is involved in the regulation of various and complex behavioural functions including regulation of circadian rhythms [14], social and sexual behaviours [15] and memory formation [16]. Contrary to other Mage genes, Maged1 is expressed in healthy somatic tissues, including the developing and adult central nervous system [13].…”

“…In addition, the relevance of Maged1 in cognitive functions has recently been enlightened in a human context. Interestingly, Maged1 binds directly to CREB in the hippocampus [16]. At the molecular level, a genome-wide analysis identified the promoter region of Maged1 as a target of chromatin remodelling induced in the NAc by a chronic cocaine treatment [19].…”

MAGED1 is a novel regulator of a select subset of bHLH PAS transcription factors

“…Maged1-null mice also show decreased levels of BDNF (brain-derived neurotrophic factor), which was attributed to impaired CREB activity [16] but may also be affected by decreased NPAS4 activity [29]. Similar to Maged1-null mice, Npas4-null mice demonstrate impaired memory formation [30].…”