Aus dem Institut für Neurophysiologie der Medizinischen Fakultät Charité – Universitätsmedizin Berlin DISSERTATION Impact of Disinhibition and Neuromodulation in Hippocampal Oscillations and LTP

aus Córdoba (Argentinien) aus Córdoba (Argentinien) aus Córdoba (Argentinien) aus Córdoba (Argentinien) Abstract Abstract Abstract Abstract Hippocampal oscillations and neuronal plasticity are involved in both cognitive functions and pathological processes. In vivo, Sharp wave-ripple (SPW-Rs) consisting of slow field potential transients with superimposed ripples by ca. 200 Hz oscillations are believed to support memory consolidation by generating long term plasticity. In hippocampal slices, repeated trains of high frequency stimulation (HFS, a long term potentiation (LTP)-protocol) induce spontaneous SPW-Rs. As the generation of LTP and SPW-Rs might be linked to each other, studies concerning the cellular mechanisms of these oscillations and their relation to activity-dependent plasticity are required. The first publication included in this doctoral thesis deals with the role of inhibition during stimulus-induced SPW-R-activity. Pharmacological full blockade of inhibition with bicuculline (BMI) transforms stimulus-induced SPW-Rs in prolonged hypersynchronous discharges called recurrent epileptiform discharges (REDs). In order to study the effects of partial reduction of inhibition, SPW-Rs were exposed to increasing concentration of nicotine, BMI and high concentrations of extracellular potassium ([K + ]o). We found that nicotine at high concentrations is able to transform SPW-Rs into REDs. This transition is related to a decrease in inhibitory conductance (GIPSP) in pyramidal cells. Similarly, low concentration of BMI transformed SPW-Rs into REDs and reduced GIPSP. Additionally, SPW-Rs were exposed to high concentrations of K +. Under these conditions, SPW-Rs do not transform into typical REDs. The GIPSP was actually increased by high K + , thus preventing the occurrence of REDs. However, treatment with high K + solution generated seizure like events (SLEs). Interestingly, the occurrence of SLEs could be lowered by previous induction of SPW-Rs. I was further interested in the effects of the neuromodulator norepinephrine (NE) on SPW-Rs. In Ul Haq et al., we show that NE has a dual effect on SPW-Rs. Activation of α-1-receptors suppresses SPW-Rs activity, this is related to a decreased presynaptic Ca2+ uptake as indicated by paired pulse ratio (PPR), analysis of coefficient of variance (CV) and measurements of Ca2+ uptake into presynaptic terminals. In contrast, activation of β-receptors enhances SPW-Rs activity. Finally, the modulatory effects of C-natriuretic peptide (CNP) in activity-dependent plasticity in area CA1 of the hippocampus were investigated. CNP, a member of the natriuretic peptides family with neuromodulatory properties, has been shown to impair stimulus induced SPW-Rs. To complete these finding, we investigated the effects of CNP in bidirectional plasticity. We show …