Altered phosphorylation, electrophysiology, and behavior on attenuation of PDE4B action in hippocampus

Abstract

BackgroundPDE4 cyclic nucleotide phosphodiesterases regulate 3′, 5′ cAMP abundance in the CNS and thereby regulate PKA activity and phosphorylation of CREB, which has been implicated in learning and memory, depression and other functions. The PDE4 isoform PDE4B1 also interacts with the DISC1 protein, implicated in neural development and behavioral disorders. The cellular functions of PDE4B1 have been investigated extensively, but its function(s) in the intact organism remained unexplored.ResultsTo specifically disrupt PDE4B1, we developed mice that express a PDE4B1-D564A transgene in the hippocampus and forebrain. The transgenic mice showed enhanced phosphorylation of CREB and ERK1/2 in hippocampus. Hippocampal neurogenesis was increased in the transgenic mice. Hippocampal electrophysiological studies showed increased baseline synaptic transmission and enhanced LTP in male transgenic mice. Behaviorally, male transgenic mice showed increased activity in prolonged open field testing, but neither male nor female transgenic mice showed detectable anxiety-like behavior or antidepressant effects in the elevated plus-maze, tail-suspension or forced-swim tests. Neither sex showed any significant differences in associative fear conditioning or showed any demonstrable abnormalities in pre-pulse inhibition.ConclusionsThese data support the use of an isoform-selective approach to the study of PDE4B1 function in the CNS and suggest a probable role of PDE4B1 in synaptic plasticity and behavior. They also provide additional rationale and a refined approach to the development of small-molecule PDE4B1-selective inhibitors, which have potential functions in disorders of cognition, memory, mood and affect.

Therapeutic targeting of 3′,5′-cyclic nucleotide phosphodiesterases: inhibition and beyond

“…delivery of a DN-PDE4A5 to the mouse hippocampus was able to rescue localized cAMP signaling deficits and hippocampus-dependent memory impairments that were caused by sleep deprivation (256)(257)(258). In contrast, overexpression of a DN-PDE4B1 in the forebrain of mice did not affect hippocampus-dependent memory, although it did enhance hippocampal long-term potentiation in male mice (259). This finding underscores the importance of understanding the role of specific PDE isoforms, because a homozygous mutation in PDE4B (Y358C) that greatly reduces activity of all PDE4B isoforms by virtue of attenuating interactions with the scaffold protein Disrupted In Schizophrenia 1 (DISC1) improves both long-term potentiation and memory as well as other mood-related behaviors (260).…”

Dominant-Negative Attenuation of cAMP-Selective Phosphodiesterase PDE4D Action Affects Learning and Behavior

“…Our transgenic mice expressed PDE4D5-D556A ( Figure 1 c) under the control of the α-calmodulin kinase II (αCaMKII) promoter [ 155 , 156 , 157 ]. They were generated specifically for this paper using techniques we described previously [ 133 ]. During breeding, the PDE4D5-D556A transgene was inherited at the expected Mendelian frequency, showing that the transgene did not produce toxicity or affect fetal viability.…”

“…We assessed basic aspects of PDE4D5-D556A mice using the SHIRPA protocol [ 158 , 159 ]. This protocol tested measurements of physical characteristics, sensorimotor reflexes, general behavior, motor responses, grip strength, and included the Rotarod test and the wire suspension test, as described [ 133 ]. Wild-type and PDE4D5-D556A transgenic mice littermates were indistinguishable in these assays.…”

“…Recently, we extended our dominant-negative approach to the functional study of PDE4 isoforms in the CNS [ 133 ]. Our first study focused on an important PDE4B isoform, specifically PDE4B1.…”

“…For this work, we developed mice that expressed a dominant-negative mutant, PDE4B1-D564A (corresponding to the D556A mutation in PDE4D5), in the murine forebrain and hippocampus. This PDE4B1-D564A-encoding transgene markedly affected behavior, as measured in open-field testing, and produced significant alterations in the phosphorylation of critical substrates and in hippocampal synaptic plasticity [ 133 ]. This and similar dominant-negative strategies [ 134 , 135 , 136 ] expand on other genetic approaches that have been used to study PDE4 function in the CNS, such as gene knockouts [ 27 , 137 , 138 , 139 , 140 , 141 , 142 , 143 ] and lentiviral siRNA [ 142 , 144 , 145 , 146 , 147 ], but are potentially more isoform-selective.…”