Prostaglandin E 2 -Mediated Attenuation of Mesocortical Dopaminergic Pathway Is Critical for Susceptibility to Repeated Social Defeat Stress in Mice

mPFC’s role in stress and anxiety provides an interface between limbic and cortical structures – regulates the stress-induced activity of the hypothalamus- pituitary-adrenal (HPA) axis – Synaptic connections with nucleus accumbens – Suppress action of amygdala via glutamatergic efferents stimulating GABAergic neurons of the amygdala Under normal conditions of fear suppression (acute stress) – the mPFC is activated and inhibits amygdala output Chronic stress – Reduction in medial PFC inhibition of the amygdala  amygdala takes control

Evidence linking mPFC to psychiatric disorders – decrease in apical dendritic material in the anterior cingulate region of mPFC in depressed patients – Stimulation of mPFC neurons supresses depression-like behavior – Depression and anxiety associated with hyperactivity of amygdala – Electrical stimulation of NAc relieves depressive symptoms – Decrease of c-Fos, FosB or ΔFosB expression in glutamatergic neurons of medial PFC – Decreased expression of immediate-early gene products suggests decrease of neuronal activation in brain region

NSAIDs have therapeutic effects in major depression EP1 is present at GABAergic terminals onto midbrain dopamine neurons EP1 stimulation potentiates inhibitory synaptic inputs Prostaglandin E 2 (PGE 2 )

How are PGs generated in the Brain? gene coding for the P2X7 receptor (P2X7R) is located on a susceptibility locus associated with major depressive disorder ATP is usually released from damaged cells as a result of oxidative stress relatively high (mM) ATP concentrations are needed to elicit PGE 2 production Repeated social defeat Prenatal stress increased IL 1β mRNA levels in the hippocampus of rats Increased Iba1-immunoreactive microglial cells IL 1β is known to decrease the affinity of corticosteroid receptors in the hippocampus increased activity of HPA axis observed in adulthood studies have reported elevated blood glucocorticoids in MDD patients as well as decreased levels PGE 2 ?

P2X7/ mice exhibited significantly lower immobility time than WT mice, as revealed by a genotype main effect P2X7 mice appeared more anxious in elevated pulse maze Decreased C-Fos in basolateral amygdala and dentate gyrus P2X7 Deficient vs Wild type Mice

Materials and Methods Mice – EP1, EP2 EP3-deficient mice – EP4 Cre recombinase mice EP4-deficient  patent ductus arteriosus (blood vessel ductus arteriosus (to lungs) doesn’t close) – COX-1 and 2 deficient Repeated social defeat stress – 7-week old male mice introduced to aggressor 10 min daily for 10 days Social interaction test – Control and defeated mice in open field chamber for 150 seconds Elevated Plus maze – Control and defeat mouse in maze for 10 min Dopaminergic lesion – 6-Hydroxydopamine

PGE2 Measurement in Subcortical Region

Production of PGE2s by microglia Quantitative RT-PCR – No change in [COX-1 mRNA] after repeated social defeat – Constitutively expressed COX-1  microglia activation COX-1 activity suppressed under normal conditions?

EP1-deficiency

Attenuation of Mesocortical Dopaminergic Pathway EP1 located at GABAergic synaptic inputs to midbrain dopamine neurons – Stimulation of EP1  inhibition of dopamine neurons Susceptibility to repeated defeat – C-Fos expression in VTA measured First social defeat=increase in c-FOS in VTA Attenuated upon 10 th defeat Recent studies have shown a greater degree of c-Fos, FosB or ΔFosB expression in glutamatergic neurons of mPFC of resilient mice following chronic predator or social defeat stress. Increased expression of these immediate-early gene products would suggest increased neuronal activation in this brain region, which might represent a pro-resilience adaptation.

Dopamine Turnover Emotional behaivor – Dopamine-innervated mPFC NAc Ratio of DOPAC/HVA to dopamine mPFC – First social defeat  increase turnover – 10 th defeat attenuated turnover NAc – Smaller initial turnover but still attenuated after repeated defeat EP1-deficiency turnover attenuation didn’t occur in mPFC but still occurred in NAc – EP1 involved in attenuation upon repeated stress not involved in stress-induced activation

Susceptible – Susceptibility receptors EP1 P2X7 Resilient – Active mesocortical dopaminergic pathway – Decreased EP1 action – Decreased P2X7 action

References Tanaka, Kohei, Tomoyuki Furuyashiki, et al. Prostaglandin E2- Mediated Attenuation of Mesocortical Dopaminergic Pathway Is Critical for Susceptibility To Repeated Social Defeat Stress in Mice. Journal of Neuroscience. (2012) Durrenberger, Pascal, Edna Grunblatt, et al. Parkinson's Disease. (2012): Boucher, A, JC Arnold, et al. Resilience and redueced C-Fos Expression in P2X7 Recetor Knockout Mice Exposed to Repeated Forced Swim Test. Neuroscience (2011): Russo, S. Murrough, J. et al. Neurobiology of resilience. (2012). Nature Neuroscience 15, Furuyashiki, T. Roles of Dopamine and Inflammation-Related Molecules in Behavioral Alterations Caused by Repeated Stress. Journal of Pharmacology Science. (2012)