C-TYPE NATRIURETIC PEPTIDE DECREASES HIPPOCAMPAL NETWORK OSCILLATIONS IN ADULT RATS IN VITRO J. M. DECKER, a A. M. WÓJTOWICZ, a R. UL HAQ, a K.-H. BRAUNEWELL, a U. HEINEMANN a,b AND C. J. BEHRENS a * a Johannes Müller-Center of Physiology, Institute of Neurophysiology, Charité-Universitätsmedizin Berlin, Tucholskystrasse 2, 10117 Berlin, Germany b NeuroCure Research Center, Charité-Universitätsmedizin Berlin, Tu- cholskystrasse 2, 10117 Berlin, Germany Abstract—C-type natriuretic peptide (CNP) is an abundant neuropeptide in the human brain and the cerebrospinal fluid. CNP is involved in anxiogenesis and exerts its effects through the natriuretic peptide receptor B (NPR-B), which is expressed in the hippocampus. Hippocampal network oscil- lations of distinct frequency bands like gamma ()-oscilla- tions and sharp wave-ripple complexes (SPW-Rs) are likely involved in various cognitive functions such as the storage of information and memory consolidation in vivo. Here, we tested the effects of CNP on distinct network oscillations in horizontal slices of rat hippocampus. We found that CNP decreased the power of stimulus- and ACh/physostigmine- induced -oscillations. In contrast to stimulus-induced -os- cillations, CNP increased the frequency of ACh-induced, per- sistent network oscillations. Moreover, the peptide hormone reduced the incidence of LTP-associated SPW-Rs in area CA3 and CA1. Immunohistochemistry indicates that the pep- tide binds to receptors expressed on a subset of GAD 65– 67- immunopositive cells in addition to binding to principal and other presumably non-neuronal cells. CNP caused a hyper- polarization of CA3 neurons increased their input resistance and decreased inhibitory conductance. Together, our data suggest that the effects of CNP on synchronized hippocam- pal network oscillations might involve effects on hippocam- pal interneurons. © 2009 IBRO. Published by Elsevier Ltd. All rights reserved. Key words: network oscillations, C-type natriuretic peptides, natriuretic peptide receptor B, gamma, sharp waves, ripples. Network oscillations in the gamma () frequency band (30 –100 Hz) represent synchronous neuronal network ac- tivities occurring throughout the neocortex and archicortex in vivo (Singer and Gray, 1995). In the hippocampal for- mation -rhythms that are nested on theta activity are most consistently present during REM sleep (Vanderwolf, 1969) and exploratory behavior (Bragin et al., 1995; Buzsaki et al., 2003). By providing a temporal template, such oscilla- tions have been proposed to constitute a fundamental mechanism for the processing, storage and retrieval of information. In vivo, hippocampal -oscillations display two distinct components: the entorhinal cortex-driven dentate gyrus oscillations (40 –100 Hz), and the intrinsic hippocam- pal -oscillations (40 Hz), which are nested in a medial septum/diagonal band-activated theta network activity (Bragin et al., 1995; Chrobak and Buzsáki, 1998; Fisahn et al., 1998). In rat hippocampal slices, -oscillations can be induced either by tetanic stimulation of the stratum pyra- midale/stratum radiatum of area CA1 or the stratum granu- losum of the DG (Traub et al., 1996; Whittington et al., 1997; Poschel et al., 2003), or pharmacologically by the activation of muscarinic receptors (Fisahn et al., 1998), group I metabotropic glutamate receptors (Whittington et al., 1995) or kainate receptors (Hajos et al., 2000; Hor- muzdi et al., 2001; Dugladze et al., 2007). Hippocampal sharp wave-ripple complexes (SPW-Rs) consist of short-lived fast ripple oscillations (140 –200 Hz), which are superimposed on slow field potential transients (Buzsaki, 1986). In vivo, SPW-Rs have been observed during slow-wave sleep and behavioral immobility (Buzsaki, 1986, 1989). It has been suggested that during SPW-Rs previously stored information is replayed, which is then transferred from the hippocampus to the neocortex to finally become long lasting during a process of memory consolidation (Squire, 1992; Buzsáki, 1998). In the recent past, several in vitro studies have reported that SPW-R-like network activity can be observed in hippocampal slices of mice and rats where they occur spontaneously (Maier et al., 2003; Colgin et al., 2005; Both et al., 2008) or where similar events can be induced by repeated stimulation that induces long-term po- tentiation (LTP) (Behrens et al., 2005). During sharp waves the fast ripple network oscillations result from synchronized discharges of hippocampal CA3 cells, and the induction of SPW-Rs is accompanied by synaptic reorganization pro- cesses within the CA3 network (Behrens et al., 2005). The C-type natriuretic peptide (CNP) and its natriuretic peptide receptor (natriuretic peptide receptor-B (NPR-B)) are highly expressed in the hippocampal regions CA1– CA3 (Herman et al., 1996; Langub Jr et al., 1995). Fur- thermore, it has been shown that in vivo CNP directly influences emotional behavior, such as anxiety and arousal (for review see; Wiedemann et al., 2000) as well as learning and memory processes (Telegdy et al., 1999). LTP is suggested to be a cellular model for learning and memory. In the hippocampus CNP has recently been shown to modulate LTP in area CA1 via pre- and postsyn- *Corresponding author. Tel: +49-30-450-52-81-49; fax: +49-30-450-52- 89-62. E-mail address: christoph.behrens@charite.de (C. J. Behrens). Abbreviations: aCSF, artificial cerebrospinal fluid; ACh, acetylcholine; CNP, C-type natriuretic peptide; IIDs, interictal discharges; LTP, long- term potentiation; NGS, normal goat serum; NPR-B, natriuretic peptide receptor B; PBS, phosphate-buffered saline; PV, parvalbumine; SL-M, stratum lacunosum-moleculare; SO, stratum oriens; SP, stratum py- ramidale; SPW-Rs, sharp wave-ripple complexes; SR, stratum radia- tum; , gamma. Neuroscience 164 (2009) 1764 –1775 0306-4522/09 $ - see front matter © 2009 IBRO. Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.neuroscience.2009.09.036 1764