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Published on: June 20, 2017
Subchronic memantine induced concurrent functional disconnectivity and altered ultra-structural tissue integrity in
S Sekar1, E Jonckers, M Verhoye
1Bio-Imaging Lab, Department of Biomedical Sciences, University of Antwerp, Campus Drie Eiken, D.UC.109, Universiteitsplein 1, 2610, Wilrijk, Belgium. sekar.sakthivel@ua.ac.be
Background:
An effective NMDA antagonist imaging model may find key utility in advancing schizophrenia drug discovery research. We investigated effects of subchronic treatment with the NMDA antagonist memantine by using behavioural observation and multimodal MRI.
Methods:
Pharmacological MRI (phMRI) was used to map the neuroanatomical binding sites of memantine after acute and subchronic treatment. Resting state fMRI (rs-fMRI) and diffusion MRI were used to study the changes in functional connectivity (FC) and ultra-structural tissue integrity before and after subchronic memantine treatment. Further corroborating behavioural evidences were documented.
Results:
Dose-dependent phMRI activation was observed in the prelimbic cortex following acute doses of memantine. Subchronic treatment revealed significant effects in the hippocampus, cingulate, prelimbic and retrosplenial cortices. Decreases in FC amongst the hippocampal and frontal cortical structures (prelimbic, cingulate) were apparent through rs-fMRI investigation, indicating a loss of connectivity. Diffusion kurtosis MRI showed decreases in fractional anisotropy and mean diffusivity changes, suggesting ultra-structural changes in the hippocampus and cingulate cortex. Limited behavioural assessment suggested that memantine induced behavioural effects comparable to other NMDA antagonists as measured by locomotor hyperactivity and that the effects could be reversed by antipsychotic drugs.
Conclusion:
Our findings substantiate the hypothesis that repeated NMDA receptor blockade with nonspecific, noncompetitive NMDA antagonists may lead to functional and ultra-structural alterations, particularly in the hippocampus and cingulate cortex. These changes may underlie the behavioural effects. Furthermore, the present findings underscore the utility and the translational potential of multimodal MR imaging and acute/subchronic memantine model in the search for novel disease-modifying treatments for schizophrenia.
Insights
Subchronic memantine, an NMDA antagonist, altered brain connectivity and structure, particularly in the hippocampus and cingulate cortex. These changes may explain behavioral effects and highlight the potential of MRI in schizophrenia drug discovery.
Area of Science:
- Neuroscience
- Pharmacology
- Radiology
Background:
- Developing effective NMDA antagonist imaging models is crucial for schizophrenia drug discovery.
- Investigating memantine's effects using behavioral observation and multimodal MRI provides insight into NMDA receptor antagonism.
Purpose of the Study:
- To investigate the effects of subchronic memantine treatment on brain structure and function using multimodal MRI.
- To explore the utility of an NMDA antagonist imaging model in schizophrenia research.
Main Methods:
- Pharmacological MRI (phMRI) mapped memantine binding sites after acute and subchronic treatment.
- Resting-state fMRI (rs-fMRI) and diffusion MRI assessed changes in functional connectivity and tissue integrity.
- Behavioral observations corroborated MRI findings.
Main Results:
- Memantine induced dose-dependent phMRI activation in the prelimbic cortex.
- Subchronic treatment affected the hippocampus, cingulate, prelimbic, and retrosplenial cortices.
- rs-fMRI showed decreased functional connectivity in hippocampal and frontal cortical structures.
- Diffusion MRI indicated ultra-structural changes in the hippocampus and cingulate cortex.
- Behavioral tests showed memantine-induced hyperactivity, reversible by antipsychotics.
Conclusions:
- Repeated NMDA receptor blockade leads to functional and ultra-structural alterations in the hippocampus and cingulate cortex.
- These alterations may underlie observed behavioral effects.
- Multimodal MRI and the memantine model show translational potential for developing novel schizophrenia treatments.
