Potential roles for Homer1 and Spinophilin in the preventive effect of electroconvulsive seizures on stress-induced CA3c dendritic retraction in the hippocampus.
Electroconvulsive therapy (ECT) remains the treatment of choice for patients with severe or drug-resistant depressive disorders, yet the mechanism behind its efficacy remains poorly characterized. In the present study, we used electroconvulsive seizures (ECS), an animal model of ECT, to identify proteins possibly involved in the preventive effect of ECS on stress-induced neuronal atrophy in the hippocampus. Rats were stressed daily using the 21-day 6h daily restraint stress paradigm and subjected to sham seizures, a single ECS on the last day of the restraint period or daily repeated seizures for 10 consecutive days during the end of the restraint period. Consistent with previous findings, dendritic atrophy was observed in the CA3c hippocampal region of chronically stressed rats. In addition, we confirmed our recent findings of increased spine density in the CA1 region following chronic restraint stress. The morphological alterations in the CA3c area were prevented by treatment with ECS. On the molecular level, we showed that the synaptic proteins Homer1 and Spinophilin are targeted by ECS. Repeated ECS blocked stress-induced up-regulation of Spinophilin protein levels and further increased the stress-induced up-regulation of Homer1. Given the roles of Spinophilin in the regulation of AMPA receptors and Homer1 in the regulation of metabotropic glutamate receptors (mGluRs), our data imply the existence of a mechanism where ECS regulate cell excitability by modulating AMPA receptor function and mGluR related calcium homeostasis. These molecular changes could potentially contribute to the mechanism induced by ECS which prevents the stress-induced morphological changes in the CA3c region.
Translational Neuropsychiatry Unit, Department of Clinical Medicine, Aarhus University, Risskov 8240, Denmark. Electronic address: heidi.muller@clin.au.dk.
Heidi
H
Kaastrup Müller
Department of Neurosurgery, Department of Clinical Medicine, Aarhus University, Aarhus C 8000, Denmark.
Dariusz
D
Orlowski
Department of Neurosurgery, Aalborg University Hospital, Aalborg 9000, Denmark.
Carsten
C
Reidies Bjarkam
Translational Neuropsychiatry Unit, Department of Clinical Medicine, Aarhus University, Risskov 8240, Denmark; Centre of Excellence for Pharmaceutical Sciences, North-West University, Potchefstroom, South Africa.
Gregers
G
Wegener
Translational Neuropsychiatry Unit, Department of Clinical Medicine, Aarhus University, Risskov 8240, Denmark.
Betina
B
Elfving
D000818:Animals; D001284:Atrophy / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control; D056547:CA1 Region, Hippocampal / Q000473:pathology / Q000503:physiopathology; D056654:CA3 Region, Hippocampal / Q000473:pathology* / Q000503:physiopathology; D002352:Carrier Proteins / Q000378:metabolism*; D002908:Chronic Disease; D003866:Depressive Disorder / Q000473:pathology* / Q000503:physiopathology / Q000628:therapy*; D004195:Disease Models, Animal; D000076122:Disks Large Homolog 4 Protein; D004565:Electroconvulsive Therapy; D000072233:Homer Scaffolding Proteins; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D008840:Microfilament Proteins / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D009474:Neurons / Q000473:pathology / Q000502:physiology; D011897:Random Allocation; D017208:Rats, Wistar; D018091:Receptors, AMPA / Q000378:metabolism; D018094:Receptors, Metabotropic Glutamate / Q000378:metabolism; D012149:Restraint, Physical; D012640:Seizures / Q000473:pathology / Q000503:physiopathology; D013315:Stress, Psychological / Q000473:pathology / Q000503:physiopathology / Q000628:therapy; D000099273:Neurabins
D002352:Carrier Proteins; D000076122:Disks Large Homolog 4 Protein; D000072233:Homer Scaffolding Proteins; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D008840:Microfilament Proteins; D009419:Nerve Tissue Proteins; D018091:Receptors, AMPA; D018094:Receptors, Metabotropic Glutamate; D000099273:Neurabins; C501449:Dlg4 protein, rat; C000606624:Homer1 protein, rat
Chronic restraint stress; Electroconvulsive seizures; Homer1; Morphology; Spinophilin