Repeated shock stress facilitates basolateral amygdala synaptic plasticity through decreased cAMP-specific phosphodiesterase type IV (PDE4) expression
Previous studies have shown that exposure to stressful events can enhance fear memory and anxiety-like behavior as well as increase synaptic plasticity in the rat basolateral amygdala (BLA). We have evidence that repeated unpredictable shock stress (USS) elicits a long-lasting increase in anxiety-like behavior in rats, but the cellular mechanisms mediating this response remain unclear. Evidence from recent morphological studies suggests that alterations in the dendritic arbor or spine density of BLA principal neurons may underlie stress-induced anxiety behavior. Recently, we have shown that the induction of long-term potentiation (LTP) in BLA principal neurons is dependent on activation of postsynaptic D1 dopamine receptors and the subsequent activation of the cyclic adenosine 5′-monophosphate (cAMP)—protein kinase A (PKA) signaling cascade. Here, we have used in vitro whole-cell patch-clamp recording from BLA principal neurons to investigate the long-term consequences of USS on their morphological properties and synaptic plasticity. We provided evidence that the enhanced anxiety-like behavior in response to USS was not associated with any significant change in the morphological properties of BLA principal neurons, but was associated with a changed frequency dependence of synaptic plasticity, lowered LTP induction threshold, and reduced expression of phosphodiesterase type 4 enzymes (PDE4s). Furthermore, pharmacological inhibition of PDE4 activity with rolipram mimics the effects of chronic stress on LTP induction threshold and baseline startle. Our results provide the first evidence that stress both enhances anxiety-like behavior and facilitates synaptic plasticity in the amygdala through a common mechanism of PDE4-mediated disinhibition of cAMP-PKA signaling.
KeywordsMacromolecular complexes Compartmentalization a-Kinase anchoring protein Basolateral amygdala Chronic stress Morphology
Compliance with ethical standards
This work was supported by funding from the National Institute of Mental Health, Grant MH069852 to DGR.
- Bureau Y, Handa M, Zhu Y, Laliberte F, Moore CS, Liu S, Huang Z, MacDonald D, Xu DG, Robertson GS (2006) Neuroanatomical and pharmacological assessment of Fos expression induced in the rat brain by the phosphodiesterase-4 inhibitor 6-(4-pyridylmethyl)-8-(3-nitrophenyl) quinoline. Neuropharmacology 51(5):974–985CrossRefPubMedGoogle Scholar
- McGirr A, Lipina TV, Mun HS, Georgiou J, Al-Miri AH, Ng E, Zhai D, Elliot C, Cameron RT, Mullings JG, Liu F, Baillie GS, Clapcote SJ, Roder JD (2016) Specific inhibition of phosphodiesterase-4B results in anxiolysis and facilitates memory acquisition. Neuropsychopharmacology 41(4):1080–1092CrossRefPubMedGoogle Scholar
- Migaud M, Charlesworth P, Dempster M, Webster LC, Watabe AM, Makhinson M, He Y, Ramsay MF, Morris RG, Morrison JH, O’Dell TJ, Grant SG (1998) Enhanced long-term potentiation and impaired learning in mice with mutant postsynaptic density-95 protein. Nature 396(6710):433–439CrossRefPubMedGoogle Scholar
- Moita MA, Rosis S, Zhou Y, LeDoux JE, Blair HT (2004) Putting fear in its place: remapping of hippocampal place cells during fear conditioning. J Neurosci 2004 Aug 4 24(31):7015–7023Google Scholar
- Ryan SJ, Ehrlich DE, Rainnie DG (2014) Morphology and dendritic maturation of developing principal neurons in the rat basolateral amygdala. Brain Struct Funct 221(2):839–854Google Scholar
- Suvrathan A, Bennur S, Ghosh S, Tomar A, Anilkumar S, Chattarji S (2014) Stress enhances fear by forming new synapses with greater capacity for long-term potentiation in the amygdala. Philos Trans R Soc Lond B Biol Sci 369(1633)Google Scholar
- Terrin A, Di Benedetto G, Pertegato V, Cheung YF, Baillie G, Lynch MJ, Elvassore N, Prinz A, Herberg FW, Houslay MD, Zaccolo M (2006) PGE(1) stimulation of HEK293 cells generates multiple contiguous domains with different [cAMP]: role of compartmentalized phosphodiesterases. J Cell Biol 175(3):441–451CrossRefPubMedPubMedCentralGoogle Scholar
- Vandesompele J, De Preter K, Pattyn F, Poppe B, Van Roy N, De Paepe A, Speleman F (2002) Accurate normalization of real-time quantitative RT-PCR data by geometric averaging of multiple internal control genes. Genome Biol 3(7):RESEARCH0034Google Scholar
- Werenicz A, Christoff RR, Blank M, Jobim PF, Pedroso TR, Reolon GK, Schröder N, Roesler R (2012) Administration of the phosphodiesterase type 4 inhibitor rolipram into the amygdala at a specific time interval after learning increases recognition memory persistence. Learn Mem 19(10):495–498CrossRefPubMedGoogle Scholar
- Zhu D, Li C, Swanson AM, Villalba RM, Guo J, Zhang Z, Matheny S, Murakami T, Stephenson JR, Daniel S, Fukata M, Hall RA, Olson JJ, Neigh GN, Smith Y, Rainnie DG, Van Meir EG (2015) BAI1 regulates spatial learning and synaptic plasticity in the hippocampus. J Clin Invest. 125(4):1497–4508CrossRefGoogle Scholar