Repeated shock stress facilitates basolateral amygdala synaptic plasticity through decreased cAMP-specific phosphodiesterase type IV (PDE4) expression

Abstract

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.

PAN‐selective inhibition of cAMP‐phosphodiesterase 4 (PDE4) induces gastroparesis in mice

“…Acutely, phosphorylation of PDE4s at a conserved C-terminal site by the extracellular signaling regulated kinase (ERK) has been shown to inhibit the activity of so-called PDE4 long forms. [90][91][92] In addition, distinct PDE4 isoforms are down-regulated in a number of pathologic conditions, such as in heart failure or atrial fibrillation, [93][94][95][96] in neurologic conditions such as depression, 97 in cancer 98 during ageing, 93 or in response to stress 99 or drug treatment. 100 In this context, while in the present study, gastroparesis was produced by decreasing PDE4 activity via pharmacologic means, our findings also open the possibility that a physiologic or pathophysiologic downregulation of PDE4 expression and/or activity may be the cause of gastroparesis in a subset of patients, given that the majority of cases remain idiopathic to date.…”

High-fructose diet initiated during adolescence does not affect basolateral amygdala excitability or affective-like behavior in Sprague Dawley rats

“…Their brains were removed and processed for slice electrophysiology as described previously [25]. Brains were immersed in ice-cold "cutting solution" consisting of (in mM): NaCl (130), NaHCO 3 (30), KCl (3.50), KH 2 PO 4 (1.10), MgCl 2 (6.0), CaCl 2 (1.0), glucose (10), ascorbate (0.4), thiourea (0.8), sodium pyruvate (2.0), and kynurenic acid (2.0).…”

“…Individual slices were transferred to a recording chamber and were visualized using a Leica DM6000 FS microscope (Leica Microsystems Inc., Bannockburn, IL, USA) as described previously [25]. Slices were continuously perfused by gravity-fed oxygenated 32 °C aCSF at a flow rate of 2-3 ml/ min.…”

“…In male Wistar rats administration of a high-fructose diet during adolescence and adulthood also increases anxiety-and depressive-like behavior [24]. The behavioral effects of the HFrD are similar to those of repeated shock stress, which in Sprague Dawley rats causes increased anxiety-like behavior and increased BLA excitability [25]. We therefore hypothesized a metabolic challenge (HFrD) would also cause increased BLA excitability in Sprague Dawley rats.…”

Late-Onset Behavioral and Synaptic Consequences of L-Type Ca2+Channel Activation in the Basolateral Amygdala of Developing Rats

“…The molecular mechanisms underlying plasticity of glutamatergic synaptic transmission in the BLA have been studied under conditions triggering anxiety-like behavioral responses and/or the acquisition and consolidation of fear memories (Manzanares et al, 2005;Ryan et al, 2018). Furthermore, it has been reported that activation of BLA triggered by behavioral training induces a transient increase in mRNA expression of IEGs c-fos, Homer 1a and arc (Knapska et al, 2007;Imamura et al, 2011;Nonaka et al, 2014;Rajbhandari et al, 2016).…”