Enhanced long‐term potentiation and impaired learning in phosphodiesterase 4D‐knockout (PDE4D^−/−) mice

Abstract

Elevation of intracellular cyclic adenosine monophosphate (cAMP) concentrations and subsequent regulation of downstream target gene expression through phosphorylation of cAMP-responsive element binding protein (CREB) is hypothesized to underlie the mechanism(s) of long-term memory (LTM) formation. The phosphodiesterase 4 (PDE4) enzyme family is believed to play a key role in LTM by regulating cAMP levels. Thus far, four PDE4 isoforms have been identified (PDE4A, B, C and D); however, the requisite involvement of each of these isoforms in mediating LTM has yet to be elucidated. In the present study, genetic knockout mice were used to investigate the involvement of the PDE4D isoform in both in vitro and in vivo models of learning and memory. Hippocampal synaptic transmission measured electrophysiologically in CA1 slice preparations was similar between wild-type and PDE4D (-/-) mice yet, relative to wild-type controls, knockout mice displayed enhanced early long-term potentiation (LTP) following multiple induction protocols. Interestingly, the PDE4D (-/-) animals exhibited significant behavioral deficits in associative learning using a conditioned fear paradigm as compared with control littermates. The impairment in fear conditioning observed in the PDE4D (-/-) mice could not be attributed to differences in acquisition of the task, alterations in locomotor activity or effects on shock sensitivity. Overall, the in vitro and in vivo alterations in synaptic plasticity observed in the PDE4D (-/-) mice may be explained by adaptive responses occurring throughout development, and suggest that the PDE4D isoform may be an important mediator of LTM formation.

Synthetic microRNA-mediated downregulation of Nogo-A in transgenic rats reveals its role as regulator of synaptic plasticity and cognitive function

“…Although generally increased hippocampal LTP correlates with improved learning and memory, pathological and prolonged increase in LTP may also lead to cognitive defects (50)(51)(52)(53)(54). The perseveration that we observed could indicate an effect of Nogo-A knockdown on memory, which is currently being analyzed in more detail.…”

Regulation of amygdalar PKA by β-arrestin-2/phosphodiesterase-4 complex is critical for fear conditioning

“…Evidence has demonstrated that ␤-arrestins can form stable complexes with PDE-4s in the desensitization system independent of agonist treatment (31). Behavior experiment also implicated the role of PDE-4, especially PDE-4D, in amygdala-dependent fear conditioning responses (32,33,38). Although ␤-arrestin-2 is ubiquitously expressed in CNS, Arrb2 Ϫ/Ϫ mice exhibit impaired fear conditioning and normal Morris water maze.…”

Phosphodiesterase-4 inhibitors ameliorates cognitive deficits in deoxycorticosterone acetate induced hypertensive rats via cAMP/CREB signaling system

“…The authors also investigated the PDE-4 subtypes such as PDE-4 A, B and D (Houslay and Milligan, 1997), which are distributed throughout the brain (Perez-Torres et al, 2000;Bian et al, 2004), Specifically, PDE-4 A is highly expressed in rat hippocampus CA1 sub-region ; PDE-4B is predominantly present in the amygdala, hypothalamus, striatum, frontal cortex and olfactory bulb as well as hippocampus (Dlaboga et al, 2006;Zhang et al, 2008); PDE-4 C is minimally expressed in the CNS ; PDE-4D is expressed in hippocampal CA1 region (Zhang et al, 2002;Rutten et al, 2008b). All these subtypes are selective for cAMP (Rutter et al, 2014).…”