Adrenergic Modulation of Sharp Wave-Ripple Activity in Rat Hippocampal Slices R. Ul Haq, 1 A. Liotta, 1 R. Kovacs, 1 A. Ro ¨ sler, 1 M.J. Jarosch, 1 U. Heinemann, 1,2 and C.J. Behrens 1 * ABSTRACT: Norepinephrine (NE) has been shown to facilitate learning and memory by modulating synaptic plasticity in the hippocampus in vivo. During memory consolidation, transiently stored information is transferred from the hippocampus into the cortical mantle. This process is believed to depend on the generation of sharp wave-ripple complexes (SPW-Rs), during which previously stored information might be replayed. Here, we used rat hippocampal slices to investigate neuromodulatory effects of NE on SPW-Rs, induced by a standard long-term potentiation (LTP) protocol, in the CA3 and CA1. NE (10–50 lM) dose-dependently and reversibly suppressed the generation of SPW-Rs via activation of a1 adrenoreceptors, as indicated by the similar effects of phenylephrine (100 lM). In contrast, the unspecific b adrenoreceptor agonist isoprotere- nol (2 lM) significantly increased the incidence of SPW-Rs. Furthermore, b adrenoreceptor activation significantly facilitated induction of both LTP and SPW-Rs within the CA3 network. Suppression of SPW-Rs by NE was associated with a moderate hyperpolarization in the majority of CA3 pyramidal cells and with a reduction of presynaptic Ca 21 uptake in the stratum radiatum. This was indicated by activity-dependent changes in [Ca 21 ] o and Ca 21 fluorescence signals, by changes in the paired pulse ra- tio of evoked EPSPs and by analysis of the coefficient of variance. In the presence of NE, repeated high frequency stimulation (high-frequency stimulation (HFS)) failed to induce SPW-Rs, although SPW-Rs appeared following washout of NE. Together, our data indicate that the NE-medi- ated suppression of hippocampal SPW-Rs depends on a1 adrenoreceptor activation, while their expression and activity-dependent induction is facilitated via b1-adrenoreceptors. V V C 2011 Wiley Periodicals, Inc. KEY WORDS: norepinephrine; alpha1 adrenoreceptor; beta1 adrenoreceptor; presynaptic; calcium fluorescence; LTP INTRODUCTION Norepinephrine (NE) is released in the hippocampus due to abundant noradrenergic input from the locus coeruleus (LC) (Loy et al., 1980) and has been shown to be involved in learning and memory (ini-Stula et al., 1984; Devauges and Sara, 1991; Roullet and Sara, 1998; Murchi- son et al., 2004; Tronel et al., 2004; Kemp and Manahan-Vaughan, 2008; Lemon et al., 2009) (for review, see (Sara, 2009). In the hippo- campus, a key structure for the acquisition and con- solidation of declarative memory traces, NE is released during novelty detection when neuronal activity is enhanced in the locus coeruleus (LC) (Sara et al., 1994). So far, little is known about mechanisms by which NE modulates distinct hippocampal network oscillations associated with explorative behavior and memory consolidation. As previously shown in vivo, costimulation of the perforant path and the amygdala facilitates induction of LTP in the dentate gyrus (DG) via b-adrenoreceptors, presumably due to amygdala stimulation-dependent activation of the LC (Bergado et al., 2007). In hippocampal slices, NE has been shown to facilitate induction of LTP in the DG (Lacaille and Harley, 1985; Stanton and Sarvey, 1985; Kitchigina et al., 1997) and in the CA3 and CA1 regions (Hopkins and Johnston, 1988; Heginbotham and Dunwiddie, 1991; Katsuki et al., 1997; Lin et al., 2003). Moreover, NE increases intrinsic excitability of CA1 pyramidal cells via b-adrenoreceptor activation (Madison and Nicoll, 1986; Gray and Johnston, 1987). In contrast, a-adrenoreceptor activation has been shown to decrease excitatory transmitter release in the CA3 of organotypic slice cultures (Scanziani et al., 1993). During memory formation, the hippocampus dis- plays distinct patterns of synchronized network activ- ity. Importantly, memory consolidation is based on the reactivation of previously stored information where hippocampal neurons that fire together during exploratory behavior tend to fire together again during subsequent sleep (Pavlides and Winson, 1989; Wilson and McNaughton, 1994). This replay has been shown to occur during sharp wave-ripple complexes (SPW- Rs) (Kudrimoti et al., 1999), which consist of sharp waves superimposed by fast ripple oscillations (Chrobak et al., 2000) and predominantly occur dur- ing consummatory behavior and slow wave sleep (Buzsaki, 1986; Buzsa ´ki, 1998). Similar events have been recorded in hippocampal slices of mice and rats where SPW-Rs occur spontaneously (Maier et al., 2003; Both et al., 2008; Behrens et al., 2005) or can be induced by recurrent stimulation protocols (Beh- rens et al., 2005). In our previous work we showed that both theta burst stimulation (TBS) and high fre- quency stimulation (HFS) were able to induce SPW- Rs. Both protocols, which are known to reliably 1 Institute of Neurophysiology, Charite ´ - Universita ¨tsmedizin Berlin, Charite ´platz 1, D 10117 Berlin, Germany; 2 NeuroCure Research Center, Charite ´ - Universita ¨tsmedizin Berlin, Charite ´platz 1, D 10117 Berlin, Germany Ul Haq and A. Liotta contributing equally to this work. Grant sponsor: Exzellence cluster NeuroCure; Grant number: GRK 1123; Grant sponsors: Hertie Foundation, DAAD, HEC (Pakistan). *Correspondence to: Dr. Christoph J. Behrens, Institute for Neurophysiology, Center for Physiology, Charite ´ - Universita ¨tsmedizin Berlin, Oudenarder Strasse 16, 13347 Berlin, Germany. E-mail: christoph.behrens@charite.de Accepted for publication 11 November 2010 DOI 10.1002/hipo.20918 Published online 20 January 2011 in Wiley Online Library (wileyonlinelibrary.com). HIPPOCAMPUS 22:516–533 (2012) V V C 2011 WILEY PERIODICALS, INC.