Multiple Drug Treatments That Increase cAMP Signaling Restore Long-Term Memory and Aberrant Signaling in Fragile X Syndrome Models

Abstract

Fragile X is the most common monogenic disorder associated with intellectual disability (ID) and autism spectrum disorders (ASD). Additionally, many patients are afflicted with executive dysfunction, ADHD, seizure disorder and sleep disturbances. Fragile X is caused by loss of FMRP expression, which is encoded by the FMR1 gene. Both the fly and mouse models of fragile X are also based on having no functional protein expression of their respective FMR1 homologs. The fly model displays well defined cognitive impairments and structural brain defects and the mouse model, although having subtle behavioral defects, has robust electrophysiological phenotypes and provides a tool to do extensive biochemical analysis of select brain regions. Decreased cAMP signaling has been observed in samples from the fly and mouse models of fragile X as well as in samples derived from human patients. Indeed, we have previously demonstrated that strategies that increase cAMP signaling can rescue short term memory in the fly model and restore DHPG induced mGluR mediated long term depression (LTD) in the hippocampus to proper levels in the mouse model (McBride et al., 2005; Choi et al., 2011, 2015). Here, we demonstrate that the same three strategies used previously with the potential to be used clinically, lithium treatment, PDE-4 inhibitor treatment or mGluR antagonist treatment can rescue long term memory in the fly model and alter the cAMP signaling pathway in the hippocampus of the mouse model.

Nutritional status‐dependent endocannabinoid signalling regulates the integration of rat visceral information

“…; Choi et al . ). In addition ghrelin activates AMPK (Andrews, ), as observed during fasting in the NTS (Hayes et al .…”

“…Conversely, eCB-LTD is mediated by the inhibition of the cAMP-PKA pathway via activation of Gi/o proteins (Chevaleyre et al 2007). Recent studies demonstrate that elevated levels of cAMP can inhibit mTOR through a PKA-dependent mechanism (Xie et al 2011;Okunishi et al 2014;Choi et al 2016). In addition ghrelin activates AMPK (Andrews, 2011), as observed during fasting in the NTS (Hayes et al 2009), and the PKA pathway (Cuellar & Isokawa, 2011;Cavalier et al 2015).…”

Pivotal role of cAMP‐PKA‐CREB signaling pathway in manganese‐induced neurotoxicity in PC12 cells

“…The regulation of cAMP is mainly achieved by the synthesis of nucleotide cyclase and the hydrolysis of phosphodiesterase‐4 (PDE4). PDE4 is the specific means of degrading cAMP, which in turn regulates PKA signaling to interfere with cognitive function . The activity of PDE4, like other PDEs, requires the presence of a divalent cation cofactor such as Zn 2+ , Mg 2+ , or Mn 2+ .…”

“…Mn 2+ mediated a high‐affinity and near stoichiometric (R)‐rolipram binding to PDE4 . A large body of data indicates that rolipram, a specific inhibitor for PDE4, potentially can increase cAMP signaling by inhibiting cAMP breakdown to promote memory formation . However, whether rolipram competes with Mn for PDE4 binding and mediates cAMP signaling to ameliorate Mn‐induced neurotoxicity is an interesting and underexplored issue.…”

“…PDE4 is the specific means of degrading cAMP, 28,29 which in turn regulates PKA signaling to interfere with cognitive function. [30][31][32] The activity of PDE4, like other PDEs, requires the presence of a divalent cation cofactor such as Zn 2+ , Mg 2+ , or Mn 2+ . 33,34 Mn 2+ mediated a high-affinity and near stoichiometric (R)-rolipram binding to PDE4.…”