Metabotropic Glutamate Receptor and Fragile X Signaling in a Female Model of Escalated Aggression.
BACKGROUND
Escalated aggression is a behavioral sign of numerous psychiatric disorders characterized by a loss of control. The neurobiology underlying escalated aggression is unknown and is particularly understudied in females. Research in our laboratory demonstrated that repeated aggressive experience in female hamsters resulted in an escalated response to future aggressive encounters and an increase in dendritic spine density on nucleus accumbens (NAc) neurons. We hypothesized that the activation of group I metabotropic glutamate receptor signaling though the fragile X mental retardation protein (FMRP) pathway may underlie synaptic plasticity associated with aggression escalation.


METHODS
Female hamsters were given five daily aggression tests with or without prior treatment with the metabotropic glutamate receptor 5 (mGluR5) antagonist 2-methyl-6-(phenylethynyl)-pyridine. Following aggression testing, messenger RNA expression and protein levels were measured in the nucleus accumbens for postsynaptic density protein 95 (PSD-95) and SAP90/PSD-95-associated protein 3, as well as the levels of phosphorylated FMRP.


RESULTS
Experience-dependent escalation of aggression in female hamsters depends on activation of mGluR5 receptors. Furthermore, aggressive experience decreases phosphorylation of FMRP in the NAc, which is coupled to a long-term increase in the expression of the synaptic scaffolding proteins PSD-95 and SAP90/PSD-95-associated protein 3. Finally, the experience-dependent increase in PSD-95 is prevented by antagonism of the mGluR5 receptor.


CONCLUSIONS
Activation of the FMRP pathway by group I metabotropic glutamate receptors is involved in regulating synaptic plasticity following aggressive experience. The NAc is a novel target for preclinical studies of the treatment of escalated aggression, with the added benefit that emerging therapeutic approaches are likely to be effective in treating pathologic aggression in both female and male subjects.
Department of Neuroscience and Graduate Program in Neuroscience, University of Minnesota, Minneapolis, Minnesota.
Laura E
LE
Been
Department of Neuroscience and Graduate Program in Neuroscience, University of Minnesota, Minneapolis, Minnesota.
Kelsey M
KM
Moore
Department of Neuroscience and Graduate Program in Neuroscience, University of Minnesota, Minneapolis, Minnesota.
Bruce C
BC
Kennedy
Department of Neuroscience and Graduate Program in Neuroscience, University of Minnesota, Minneapolis, Minnesota. Electronic address: meisel@umn.edu.
Robert L
RL
Meisel
D000374:Aggression / Q000187:drug effects / Q000502:physiology*; D000818:Animals; D015153:Blotting, Western; D002421:Caudate Nucleus / Q000187:drug effects / Q000378:metabolism; D006224:Cricetinae; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D005260:Female; D051860:Fragile X Messenger Ribonucleoprotein 1 / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009714:Nucleus Accumbens / Q000187:drug effects / Q000378:metabolism*; D010052:Ovariectomy; D010766:Phosphorylation; D011581:Psychological Tests; D011699:Putamen / Q000187:drug effects / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D064529:Receptor, Metabotropic Glutamate 5 / Q000037:antagonists & inhibitors / Q000378:metabolism*
D018691:Excitatory Amino Acid Antagonists; D051860:Fragile X Messenger Ribonucleoprotein 1; D009419:Nerve Tissue Proteins; D011725:Pyridines; D012333:RNA, Messenger; D064529:Receptor, Metabotropic Glutamate 5; C121465:6-methyl-2-(phenylethynyl)pyridine
Aggression; Fragile X; Nucleus accumbens; PSD-95; Plasticity; mGluR5