Adrenergic modulation of sharp wave‐ripple activity in rat hippocampal slices

NeuroCure Research Center, Charité - Universitätsmedizin Berlin, Charitéplatz 1, D 10117 Berlin, Germany
Hippocampus (Impact Factor: 4.16). 03/2012; 22(3):516 - 533. DOI: 10.1002/hipo.20918


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 μM) dose-dependently and reversibly suppressed the generation of SPW-Rs via activation of α1 adrenoreceptors, as indicated by the similar effects of phenylephrine (100 μM). In contrast, the unspecific β adrenoreceptor agonist isoproterenol (2 μM) significantly increased the incidence of SPW-Rs. Furthermore, β 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 Ca2+ uptake in the stratum radiatum. This was indicated by activity-dependent changes in [Ca2+]o and Ca2+fluorescence signals, by changes in the paired pulse ratio 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-mediated suppression of hippocampal SPW-Rs depends on α1 adrenoreceptor activation, while their expression and activity-dependent induction is facilitated via β1-adrenoreceptors. © 2011 Wiley Periodicals, Inc.

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    • "area CA1 , 5 - HT still augmented the paired pulse index , pointing to a presynaptic effect . Our conclusion is further supported by the analysis of the coefficient of variance of evoked EPSPs of CA1 pyramidal neurons which were similarly affected by serotonin in normal and in disinhibited slices , as well as by 8 - 0H - DPAT . Norepinephrine ( Ul Haq et al . , 2012 ) , adenosine , cannabi - noids ( Maier et al . , 2011a ) , and the GABA B receptor agonist baclofen ( Hollnagel et al . , 2014 ) suppress SPW - Rs by impairing synaptic ef - ficacy presumably due to reduced presynaptic Ca 2þ entry . Thus it appears that all known agents able to reduce presynaptic trans - mitter release would be able to"
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    ABSTRACT: Sharp wave ripples (SPW-Rs) are thought to play an important role in memory consolidation. By rapid replay of previously stored information during slow wave sleep and consummatory behavior, they result from the formation of neural ensembles during a learning period. Serotonin (5-HT), suggested to be able to modify SPW-Rs, can affect many neurons simultaneously by volume transmission and alter network functions in an orchestrated fashion. In acute slices from dorsal hippocampus, SPW-Rs can be induced by repeated high frequency stimulation that induces long-lasting LTP. We used this model to study SPW-R appearance and modulation by 5-HT. Although stimulation in presence of 5-HT permitted LTP induction, SPW-Rs were "masked" - but appeared after 5-HT wash-out. This SPW-R masking was dose dependent with 100 nM 5-HT being sufficient - if the 5-HT re-uptake inhibitor citalopram was present. Fenfluramine, a serotonin releaser, could also mask SPW-Rs. Masking was due to 5-HT1A and 5-HT2A/C receptor activation. Neither membrane potential nor membrane conductance changes in pyramidal cells caused SPW-R blockade since both remained unaffected by combining 5-HT and citalopram. Moreover, 10 and 30 μM 5-HT mediated SPW-R masking preceded neuronal hyperpolarization and involved reduced presynaptic transmitter release. 5-HT, as well as a 5-HT1A agonist, augmented paired pulse facilitation and affected the coefficient of variance. Spontaneous SPW-Rs in mice hippocampal slices were also masked by 5-HT and fenfluramine. While neuronal ensembles can acquire long lasting LTP during higher 5-HT levels, lower 5-HT levels enable neural ensembles to replay previously stored information and thereby permit memory consolidation memory.
    Neuropharmacology 09/2015; DOI:10.1016/j.neuropharm.2015.09.026 · 5.11 Impact Factor
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    • "This indicates that during induction of LTP certain synapses increase coupling efficacy but are not yet ready to integrate their activity into a neuronal ensemble. NE blocked stimulation induced SPW-R through activation of alpha-1 receptors for NE (Ul Haq et al., 2012). The underlying mechanism seems to be related to an alteration in presynaptic release probability mediated by effects on transmitter release. "
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    ABSTRACT: Learning is a complex brain function operating on different time scales, from milliseconds to years, which induces enduring changes in brain dynamics. The brain also undergoes continuous "spontaneous" shifts in states, which, amongst others, are characterized by rhythmic activity of various frequencies. Besides the most obvious distinct modes of waking and sleep, wake-associated brain states comprise modulations of vigilance and attention. Recent findings show that certain brain states, particularly during sleep, are essential for learning and memory consolidation. Oscillatory activity plays a crucial role on several spatial scales, for example in plasticity at a synaptic level or in communication across brain areas. However, the underlying mechanisms and computational rules linking brain states and rhythms to learning, though relevant for our understanding of brain function and therapeutic approaches in brain disease, have not yet been elucidated. Here we review known mechanisms of how brain states mediate and modulate learning by their characteristic rhythmic signatures. To understand the critical interplay between brain states, brain rhythms, and learning processes, a wide range of experimental and theoretical work in animal models and human subjects from the single synapse to the large-scale cortical level needs to be integrated. By discussing results from experiments and theoretical approaches, we illuminate new avenues for utilizing neuronal learning mechanisms in developing tools and therapies, e.g., for stroke patients and to devise memory enhancement strategies for the elderly.
    Frontiers in Computational Neuroscience 02/2015; 9:1. DOI:10.3389/fncom.2015.00001 · 2.20 Impact Factor
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    • "Interestingly, in kindled animals sensitivity to norepinephrine modulation of synaptic plasticity was down-regulated in the dentate gyrus (Stanton et al., 1989). Norepinephrine also modulates synaptic plasticity via activation of b-AR in area CA3 (Villani and Johnston, 1993) and at CA3-CA1 synapses (Ul Haq et al., 2012). At CA1-subiculum synapses a cell-specific form of norepinephrine-dependent LTP was found in BS but not in RS cells (Wo´jtowicz et al., 2010). "
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    ABSTRACT: Norepinephrine acting via β-adrenergic receptors (β-AR) plays an important role in hippocampal plasticity including the subiculum which is the principal target of CA1 pyramidal cells and which controls information transfer from the hippocampus to other brain regions including the neighboring presubiculum and the entorhinal cortex (EC). Subicular pyramidal cells are classified as regular- and burst-spiking cells. Activation of β-ARs at CA1-subiculum synapses induces long-term potentiation (LTP) in burst- but not in regular-spiking cells (Wojtowicz et al., 2010). To elucidate seizure-associated disturbances in the norepinephrine-dependent modulation of hippocampal output, we investigated the functional consequences of the β-AR-dependent synaptic plasticity at CA1-subiculum synapses for the transfer of hippocampal output to the parahippocampal region in the pilocarpine model of temporal lobe epilepsy. Using single-cell and multi-channel field recordings in slices, we studied β-AR-mediated changes in the functional connectivity between CA1, the subiculum and its target-structures. We confirm that application of the β-adrenergic agonist isoproterenol induces LTP in subicular burst- but not regular-spiking cells. Due to the distinct spatial distribution of regular- and burst-spiking cells in the proximo-to-distal axis of the subiculum, in field recordings, LTP was significantly stronger in the distal than in the proximal subiculum. In pilocarpine-treated animals, β-AR-mediated LTP was strongly reduced in the distal subiculum. The attenuated LTP was associated with a disturbed polysynaptic transmission from the CA1, via the subiculum to the presubiculum, but with a preserved transmission to the medial EC. Our findings suggest that synaptic plasticity may influence target related information flow and that such regulation is disturbed in pilocarpine-treated epileptic rats. Copyright © 2014. Published by Elsevier Ltd.
    Neuroscience 12/2014; 286. DOI:10.1016/j.neuroscience.2014.11.055 · 3.36 Impact Factor
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