Pharmakologie, Toxikologie und Klinische Pharmazie

Brief Reseach Statement

Our research focuses on the function of Ca2+/Na+-activated K+ channels like BK, IK, Slo2.2/Slack, and Slo2.1 Slick in synaptic plasticity, particularly in respect learning and memory.

Current Projects

Project (1): Developmental impairment of synaptic plasticity in Slack knock-out mice

PI: Lucas Matt, Co-PI: Robert Lukowski
Co-worker: Thomas Pham, Jiaqi Yin

Learning and memory are thought to derive from synaptic plasticity which is the property of glutamatergic synapses to alter their efficiency by up- or down-regulating the density of postsynaptic AMPA receptors by endo- or exocytosis, respectively. Experimentally, we can determine the plasticity of hippocampal synapses as long-term potentiation (LTP) or long-term depression (LTD).

The sodium-activated potassium channel Slack (sequence like a calcium-activated K+-channel, KNa2.2, Slo2.2) modulates resting membrane potential and thus neuronal excitability levels. Slack is highly expressed in the hippocampus, a brain region crucial for the processing and consolidation of spatial memory. Slack knockout mice (Slack-/-) were found to display specific deficiencies in hippocampus-dependent memory, particularly in the reversal learning of previously acquired tasks, a learning paradigm associated with impaired hippocampal LTD.

Using field recordings of excitatory postsynaptic potentials (fEPSP) as well as whole-cell patch-clamp recordings from hippocampal pyramidal cells we investigate the underlying physiological defects leading to this phenotype. On a molecular level, this investigation is supported by state-of-the-art imaging and biochemical methods.

Project (2): The function of BK in hippocampal synaptic plasticity

PI: Lucas Matt, Co-PI: Robert Lukowski
Co-worker: Thomas Pham, Stefanie Simonsig

Despite its importance and being a widely studied molecule, very little is known about the function of the calcium-activated K+-channel of high conductance (BK, Slo1, KCa1.1) in the function and plasticity of central glutamatergic synapses. In this project, we use Cre-LoxP-mediated conditional deletion of BK channels from different neuronal populations in the hippocampus to assess its physiological role for excitability, firing properties, synaptic plasticity, and behavior.

Project (3): The role of BK in the hypothalamic control of feeding and satiety

PIs: Lucas Matt, Robert Lukowski
Co-worker: Clement Kabagema-Bilan, N.N.

Mice lacking the calcium-activated K+-channel of high conductance (BK, Slo1, KCa1.1) are protected from weight gain under a high-fat diet. This protection from dietary-induced obesity is in part due to a function of BK channels in adipocytes (Illison et al. Diabetes. 2016;3621-35). Another part of the effect, however, is due to the channels role in the hypothalamus, the central regulator of energy homeostasis. Using cell-type specific odeletion of BK channels from different hypothalamic neuronal population, we strive to characterize BK channel function the responsible cell types. Using this knowledge, it might be possible to harness BK's role in feeding control to counteract the obesity epidemic.

Project (4): NO/cGMP-mediated modulation of nuclear BK channels

PIs: Lucas Matt, Peter Ruth
Co-worker: Nadine Rieth, Clement Kabagema-Bilan

Functional calcium-activated K+-channels of high conductance (BK, Slo1, KCa1.1) are found in the nuclear envelope of cortical neurons, where they are thought to regulate RyR-mediated Ca2+ entry into the nucleoplasm. Nucleoplasmic Ca2+ is an important regulator of neuroprotective gene expression. The cGMP-activated protein kinase I (cGKI) is one of the major regulators of BK channel activity and is also found in neuronal nucleoplasm. The aim of this project is to establish a functional link between the NO-cGMP-cGKI signaling cascade and the BK-mediated control of nucleoplasmic Ca2+ levels. These goals will be achieved by utilizing state-of-the-art genetically encoded biosensor for Ca2+, K+, cGMP, and kinase activity in primary neuronal cultures and isolated nuclei.