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Assessment of Memory Function in Pilocarpine-induced Epileptic Mice
Published on: June 4, 2020
Gene expression analysis indicates reduced memory and cognitive functions in the hippocampus and increase in synaptic
Peter Petschner1,2, Viola Tamasi3, Csaba Adori1,4
1Department of Pharmacodynamics, Semmelweis University, Nagyvarad ter 4., Budapest, H-1089, Hungary.
Background:
3,4-methylenedioxymethamphetamine (MDMA, "ecstasy") is a widely used entactogenic drug known to impair cognitive functions on the long-run. Both hippocampal and frontal cortical regions have well established roles in behavior, memory formation and other cognitive tasks and damage of these regions is associated with altered behavior and cognitive functions frequently described in otherwise healthy MDMA users. Meanwhile, in post-traumatic stress disorder (PTSD) patients seem to benefit from therapeutic application of the drug, where damage in hippocampal cue extinction may play a role. The aim of this study was to examine the hippocampus, frontal cortex and dorsal raphe of Dark Agouti rats with gene expression arrays (Illumina RatRef bead arrays) looking for possible mechanisms and new candidates contributing to the consequences of a single dose of MDMA (15 mg/kg) 3 weeks earlier.
Results:
The number of differentially expressed genes in the hippocampus, frontal cortex and the dorsal raphe were 481, 155, and 15, respectively. Gene set enrichment analysis of the microarray data revealed reduced expression of 'memory' and 'cognition', 'dendrite development' and 'regulation of synaptic plasticity' gene sets in the hippocampus, parallel to the downregulation of CaMK II subunits, glutamate-, CB1 cannabinoid- and EphA4, EphA5, EphA6 receptors. Downregulated gene sets in the frontal cortex were related to protein synthesis, chromatin organization, transmembrane transport processes, while 'dendrite development', 'regulation of synaptic plasticity' and 'positive regulation of synapse assembly' gene sets were upregulated besides elevated levels of a CaMK II subunit and NMDA2B glutamate receptor. Changes in the dorsal raphe region were mild and in most cases not significant.
Conclusion:
The present data raise the possibility of new synapse formation / synaptic reorganization in the frontal cortex 3 weeks after a single neurotoxic dose of MDMA. In contrast, a prolonged depression of new neurite formation in the hippocampus is proposed by downregulations of members in long-term potentiation pathway and synaptic plasticity emphasizing the particular vulnerability of this brain region and proposing a mechanism responsible for cognitive problems in healthy individuals. At the same time, these results underpin benefits of MDMA in PTSD, where the drug may help memory extinction.
Insights
A single dose of 3,4-methylenedioxymethamphetamine (MDMA) impaired hippocampus function but promoted frontal cortex changes. These findings may explain cognitive issues in users and benefits in PTSD treatment.
Area of Science:
- Neuroscience
- Pharmacology
- Molecular Biology
Background:
- 3,4-methylenedioxymethamphetamine (MDMA) is known to impair cognitive functions long-term.
- Hippocampal and frontal cortical regions are crucial for cognition; damage is linked to altered behavior in MDMA users.
- MDMA shows therapeutic potential in PTSD, possibly involving hippocampal cue extinction mechanisms.
Purpose of the Study:
- To investigate the molecular mechanisms underlying the long-term effects of a single MDMA dose.
- To examine gene expression changes in the hippocampus, frontal cortex, and dorsal raphe.
- To identify potential molecular candidates contributing to MDMA's cognitive consequences.
Main Methods:
- Gene expression arrays (Illumina RatRef bead arrays) were used.
- Analysis focused on hippocampus, frontal cortex, and dorsal raphe of Dark Agouti rats.
- A single MDMA dose (15 mg/kg) was administered 3 weeks prior to analysis.
Main Results:
- Significant gene expression changes were observed: 481 in the hippocampus, 155 in the frontal cortex, and 15 in the dorsal raphe.
- Hippocampal gene sets related to memory, cognition, dendrite development, and synaptic plasticity were downregulated.
- Frontal cortex showed upregulated gene sets for dendrite development and synaptic plasticity, alongside elevated CaMK II and NMDA2B receptor levels.
Conclusions:
- MDMA may induce synaptic reorganization in the frontal cortex.
- Prolonged depression of neurite formation in the hippocampus suggests a mechanism for cognitive deficits.
- Findings support MDMA's therapeutic potential in PTSD by potentially aiding memory extinction.
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