Laboratory of Molecular Neurophysiology and Plasticity

Group Leader

Mai Marie Holm
Associate professor, PhD
More information

Laboratory of Molecular Neurophysiology and Plasticity

RESEARCH
The main focus of our research is molecular neurophysiology in the hippocampus of rodents. Hippocampus is a key structure of the brain involved in learning and memory which is especially suited for laboratory analyses of the molecular mechanisms underlying brain processes. A thorough characterization of the functional properties of the synapses in the mammalian brain is fundamental for our understanding of the healthy as well as the diseased brain. Ultimately our studies may help future patients suffering from brain-related disorders.

RESEARCH INTERESTS
A main ongoing project focuses on a transgenic mouse model where a synaptic protein (SORCS3) has been genetically removed (Breiderhoff et al., 2013, PLoS ONE). So far the exact function of the receptor is unknown, but strong expression has been proven in the hippocampal area (Hermey et al., 2004, J. Neurochem.). Consequently we take advantage of field recordings in the CA1 and dentate gyrus of acutely isolated brain sections. We have identified key roles of SORCS3 in synaptic plasticity which point at essential functions for the receptor in learning and memory. Now the aim is to pin-point the function in greater details by exploring potential interaction partners in the synapse.

Another line of studies aims to understand the underlying pathological mechanisms in the brain of a mouse model of the devastating neurodegenerative disease, amyotrophic lateral sclerosis (ALS). This model, the wobbler mouse, was genetically characterized by Dr. Thomas Schmitt-John and co-workers in 2005 (Nature Genetics). Here we employ electrophysiological analyses in the hippocampus to identify neurophysiological changes at different stages of disease progression in the brain of this mouse model. Interestingly, our data point at hippocampal hyperexcitability which is most pronounced in the brain of the symptomatic animals (Thielsen et al., 2013, PLoS ONE). Research is in progress to characterize the synaptic impairments in greater details, also including relevant pharmacological tools such as the only ALS-drug riluzole. 

A third current project involves analyses of positive allosteric modulators of the AMPA receptors, a subgroup of the glutamate receptors. The AMPA receptors are key players in synaptic plasticity and their open state is stabilized in the presence of positive allosteric modulators. This interaction results in a strengthening of the synaptic transmission and a lowering of the induction threshold together with increased magnitude of the long-term potentiation (LTP). In more complex systems the molecules improve learning and memory and increase BDNF expression associated with a range of positive effects on the brain. Evidence from the literature suggests possible roles as future therapeutic agents in psychiatric disorders (Lynch and Gall, 2006, TRENDS in Neurosci.). We take advantage of the compounds as pharmacological tools in our studies of synaptic plasticity in the hippocampus of rodent brain slices. Recently we completed a detailed analysis of a novel allosteric modulator with an interesting dualistic profile (Christiansen et al., 2015, Neuroscience). These data will strengthen our knowledge of the modulators and facilitate future applications of the compounds as manipulators of synaptic plasticity in the human brain.   

METHODOLOGIES
Brain slice electrophysiology in the hippocampus
Immunohistochemical techniques
Extracellular field recordings
Patch-clamp electrophysiology
PCR based genotyping
Long-term depression (LTD) and long-term potentiation (LTP)

COLLABORATORS & Centers

  • Ulrik Bølcho and Anders Nykjær, DANDRITE, Department of Biomedicine, AU
  • Jan Egebjerg Jensen, Science and Technology, AU
  • Morten Skovgaard Jensen, Department of Biomedicine, AU
  • Jette Sandholm Kastrup, Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen
  • Thomas Schmitt-John, Science and Technology, AU
  • Karin Lykke-Hartmann, PUMPKIN, AU
  • Kim Henningsen and Ove Wiborg, Translational Neuropsychiatric Unit, Risskov, AU
  • Rafael Fernández-Chacón, Sevilla, Spain

RESEARCH GROUP MEMBERS
Gitte Bundgaard Christiansen, PhD student; Signe Rode Andreasen, PhD student; Lasse Kruse, master student and Lone Overgaard, technician. Typically, the group supervises a number of bachelor students and master students.

 

 

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Revideret 03.08.2016