Rhythmogenese und synaptische Plastizität im entorhinalen Kortex-Hippokampus-Komplex
Final Report Abstract
The entorhinal cortex-hippocampus complex is involved in spatial navigation and formation of explicit memories. The aim ofthe project was to obtain more insight into mechanisms, which improve formafion of memory and of memory consolidation. This implies also analysis of mechanisms, which might both improve and disturb memory formation. In addition, we wanted to get insight into disturbances of the network activity, particulariy involved in the acquisition and consolidation of declarative memory traces, which might lead to understanding of amnesia and mental disorders. In this context, it was important to study mechanisms involved in the generation and modulation of network oscillatory activities. Our study suggest that 1 Hz stimulation of the direct cortical input (dCI) induced homosynaptic long-term depression (LTD) and that 1 Hz stimulation of the dCl induces a long-lasting augmentation of stratum radiatum-induced population spikes in area CAI (heterosynaptic LTP). Additionally, we show that homosynaptic effects depend on activation of GABAB and kainate receptors, whereas the heterosynaptic effects are GABAA and mGluR- dependent. Based on the observations that induction of LTP in the recurrent CA3 network may facilitate the generation of sharp wave-ripple complex (SPW-Rs), we tested the hypothesis that monoamines, which facilitate the induction of LTP, also promote the induction of SPW-Rs. We tested for effects of dopamine, NE and serotonin. We found that ß-adrenoreceptor agonists and Dl agonists for dopamine could facilitate induction of SPW-Rs. Likewise, when gamma oscillations had been induced by ACh, the induction of SPW-Rs was facilitated. This effect was in part mediated by nicofinergic mechanisms and may be due to partial disinhibition through activation of non parvalbumine-positive basket cells expressing nicotinergic receptors. Since repeated HFS, as used for the induction of SPW-Rs in our experiments, is reminiscent of protocols used to induce kindling epilepsy when HFS is applied at much higher stimulus intensities and often also unphysiological artificial cerebrospinal fluid compositions, we investigated differences between SPW-Rs and epileptiform discharges. Our findings indicate that in vitro SPW-Rs do not represent classical interictal discharges, and that increased GABAergic inhibition onto CA3 pyramidal cells, as observed under conditions of elevated [K+]o, prevents the transition of SPW-Rs into REDs and decreases the likelihood for the induction of seizure-like events. We next analyzed the mechanisms which regulate incidence of SPW-Rs. First, we demonstrated the incidence of SPW-Rs, but not the ripple frequency is regulated by 4-AP- sensitive potassium current. In the presence of 5 mM [K*]o, the incidence of SPW-Rs may also be increased due to induced bursting behavior. This may be due to reduced efficacy of a Ca^2+ dependent K+ conductance and of Kv2 channels, which encode for M-current. Whether these channels are involved in regulating the incidence of SPW-Rs is presently unclear. We found that 5-HT and NE block stimulus-induced SPW-Rs. Our data indicate that the NE- mediated suppression of hippocampal SPW-Rs depends on a1 adrenoreceptor activation while their expression and activity-dependent induction together with induction of LTP is facilitated via ß1-adrenoreceptors. In contrast to NE and 5-HT, ACh combined with 2 pM physostigmine rapidly blocked previously induced SPW-Rs and replaced them by network oscillations in gamma range in horizontal slices and by theta activity in longitudinal slices. Following washout of ACh, NE and 5-HT SPW-Rs reappeared with properties, which were very similar to those under control conditions. We found that SPW-Rs are reversibly blocked following hypoxia when oxygen tension was lowered below a critical level. This effect was due to a reduced presynaptic transmitter release within the CA3 network. Since SPW-Rs may be importantly involved in the transfer of transiently stored information in the hippocampus throughout the cortical mantle in vivo, our data may contribute to a better understanding of hypoxia-induced amnesia.
Publications
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Induction of sharp wave-ripple complexes in vitro and reorganization of hippocampal networks. Nat Neurosci. 2005 Nov;8(11):1560-7
Behrens CJ, van den Boom LP, de Hoz L, Friedman A, Heinemann U
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Orthogonal arrangement of rhythm-generating microcircuits in the hippocampus. Proc Natl Acad Sci U S A. 2005 Sep 13; 102(37): 13295-30
Gloveli T, Dugladze T, Rotstein HG, Traub RD, Monyer H, Heinemann U, Whittington MA, Kopell NJ
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(2007) Acute and longterm effects of MK-801 on direct cortical input evoked homosynaptic and heterosynaptic plasticity in the CAI region of the female rat. Eur J Neurosci 26:2873-2883
Wohrl R, Eisenach S, Manahan-Vaughan D, Heinemann U, von Haebler D
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(2007) Effects of the GABA(A) receptor antagonists bicuculline and gabazine on stimulus-induced sharp wave-rippie complexes in adutt rat hippocampus invitro. EurJ Neurosci25:2170-2181
Behrens CJ, van den Boom LP, Heinemann U
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(2007) Hypoxia suppresses kainate-induced gamma-oscillations in rat hippocampal slices. NeuroReport 18:1827-1831
Fano S, Behrens CJ, Heinemann U
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(2007) Low-frequency stimulation of the direct cortical input to area CAI induces homosynaptic LTD and heterosynaptic LTP in the rat hippocampal-entorhinal cortex slice preparation. EurJ Neurosci 25:251-258
Wöhrl R, von Haebler D, Heinemann U
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lmpaired hippocampal rhythm ogenesis in a mouse model of mesial temporal lobe epilepsy. Proc Natl Acad Sci USA. 2007 Oct 30; 104(44): 17530
Dugladze T, Vida I, Tort AB, Gross A, Otahal J, Heinemann U, Kopell NJ, Gloveli T
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lncreased inhibitory input to CAI pyramidal cells alters hippocampal gamma frequency oscillations in the MK-801 model ofacute psychosis. Neurobiol Dis. 2007 Mar;25(3):545-52
Kehrer C, Dugladze T, Maziashvili N, Wojtowicz A, Schmitz D, Heinemann U, Gloveli T
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(2008) C-Type natriuretic peptide modulates pre- and postsynaptic properties in hippocampal area CA1 in vitro. Biochem Biophys Res Commun 377:820-825
Decker JM, Wojtowicz A, Heinemann U, Braunewell KH
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(2008) Effects of 4-aminopyridine on sharp wave-ripples in rat hippocampal slices. NeuroReport 19:491-496
Richter JP, Behrens CJ, Chakrabarty A, Heinemann U
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Gamma oscillations and spontaneous network activity in the hippocampus are highly sensitive to decreases in p02 and concomitant changes in mitochondrial redox state. J Neurosci. 2008 Jan 30;28(5):1153-62
Huchzermeyer C, Albus K, Gabriel HJ, Otahal J, Taubenberger N, Heinemann U, Kovács R, Kann O
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(2009) C-type natriuretic peptide decreases hippocampal network oscillations in adult rats in vitro. Neuroscience 164:1764-1775
Decker JM, Wojtowicz AM, Ul HR, Braunewell KH, Heinemann U, Behrens CJ
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(2009) Effects of XE991, retigabine, losigamone and 207288 on kainate-induced theta-like and gamma network oscillations in the rat hippocampus in vitro. Brain Res 1295:44-58
Boehlen A, Kunert A, Heinemann U
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(2009) Monoamines block kainate- and carbachol-induced gamma-oscillations but augment stimulus-induced gamma-oscillations in rat hippocampus in vitro. Hippocampus 19:273-288
Wojtowicz AM, van den BL, Chakrabarty A, Maggio N, Haq RU, Behrens CJ, Heinemann U
