Behavioral and neurochemical characterization of mice deficient in the phosphodiesterase-1B (PDE1B) enzyme
Introduction
The cyclic nucleotides cAMP and cGMP are second messengers mediating intracellular signal transduction. A key element in regulation of these signaling pathways is metabolic inactivation of cyclic nucleotides by cyclic nucleotide phosphodiesterases (PDEs) (for reviews, Soderling and Beavo, 2000, Bender and Beavo, 2006). In mammals, PDEs comprise a superfamily of enzymes divided into 11 families that are differentially localized throughout the organism. The ability to selectively regulate cyclic nucleotide signaling through pharmacological manipulation of these enzymes may offer unique therapeutic opportunities.
Type 1 cyclic nucleotide phosphodiesterases (PDE1) are highly enriched in brain and are characterized by Ca2+-dependent stimulation via the Ca2+-binding protein calmodulin (CaM). Three PDE1 isoforms have been identified (PDE1A, PDE1B, and PDE1C) and all are expressed within the central nervous system. PDE1A is expressed throughout the brain, with high levels in the hippocampus, cerebellum and low levels in the striatum (Borisy et al., 1992, Yan et al., 1994). In situ hybridization and immunocytochemistry demonstrate high levels of PDE1B mRNA and/or protein in the caudate putamen, nucleus accumbens, olfactory tubercle and dentate gyrus, moderate levels in the olfactory bulb and cortex and lower levels in various other brain areas including the globus pallidus, substantia nigra, and hypothalamus (Polli and Kincaid, 1992, Polli and Kincaid, 1994, Repaske et al., 1993, Yan et al., 1994). The expression pattern of PDE1B observed within the caudate putamen is similar to that found for the D1 dopamine receptor and correlates strongly with brain areas that are richest in dopaminergic innervation, suggesting an important role in antagonism of cAMP-regulated signaling in dopaminoceptive neurons. PDE1C is expressed primarily in olfactory epithelium, cerebellum and striatum (Yan et al., 1995, Yan et al., 1996).
Previous studies have reported the generation and initial characterization of the PDE1B knockout mouse (Reed et al., 2002). In this initial study, PDE1B knockout mice maintained on a C57BL6/129svj genetic background demonstrated altered spontaneous locomotor activity and Morris water maze behavior. Gender differences in locomotor activity were also reported for PDE1B knockout mice. The aim of the present experiments was to backcross PDE1B knockout mice onto a congenic C57BL/6N genetic background. Congenic male and female PDE1B wild-type and knockout mice would then be assessed in a variety of well-established behavioral tests including spontaneous locomotor activity, hot plate (analgesia), forced swim test (depression-like behavior), elevated plus maze (anxiety-like behavior), passive avoidance (cognition) and conditioned avoidance responding (acquisition and response to the suppressant effects of an antipsychotic drug). High levels of PDE1B are expressed within the striatal medium spiny neurons (Repaske et al., 1993, Furuyama et al., 1994), the activity of which are regulated by both cortical/thalamic glutamatergic inputs and midbrain dopaminergic projections. Previous studies have reported that PDE1B knockout mice demonstrate an exaggerated response to a single dose of METH (Reed et al., 2002, Ehrman et al., 2006). In order to investigate the interaction of PDE1B with both dopaminergic and glutamatergic systems, the locomotor response of PDE1B knockout mice to multiple doses of DA-releasing agents (METH and AMPH) and NMDA receptor antagonists (MK-801 and PCP) was also examined. Finally, in order to further explore a potential association between PDE1B and dopamine, we have examined the regional brain content of monoamines and their respective metabolites in these mice.
Section snippets
Animals
Breeding pairs of PDE1B wild-type and knockout mice were obtained from Dr. David Repaske (Cincinnati, OH) and a colony was established and maintained at Charles River Laboratories (CRL, Wilmington, MA). All PDE1B wild-type and knockout mice were selected from the tenth generation backcross onto a C57BL/6N (CRL) background. Mice generated for the present studies were bred using a knockout × knockout and wild-type × wild-type breeding strategy. Adult mice were housed in groups of 5–10 at ambient
Behavioral observation
No gross abnormalities were detected in PDE1B knockout mice. All mice appeared healthy, active and well groomed. No differences were observed between wild-type and knockout mice in a functional observational battery. Gross alterations of locomotor activity and reactivity to auditory and tactile stimulation were not apparent in the mutant mice. No tremors or convulsions were observed. All reflexes appeared normal.
Body weight for male and female PDE1B wild-type and knockout mice was assessed over
Discussion
Previous studies have reported the generation and initial behavioral characterization of PDE1B knockout mice (Reed et al., 2002). Although the present studies are an extension of this previous work, one significant difference between these two studies is the genetic background of the knockout mouse. In the initial study, PDE1B mice were backcrossed to C57Bl/6N (CRL) for three generations and then maintained on a mixed C57BL6/129svj genetic background for behavioral evaluation. In the present
Acknowledgments
Portions of this work were presented at the Society for Neuroscience, San Diego, CA, November 2001. The authors would like to thank the Genetically Modified Mouse breeding group for assistance with these studies.
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