Login |

B6 - Impact of psychiatric-disease-related genetic variations on PFC network function

Principal investigator(s):

Abteilung Computational Neuroscience
Zentralinstitut für Seelische Gesundheit (ZI)
J5, D-68159 Mannheim


Projects within the BCCN:

The main goal of this project was to devise an experimental approach for analyzing psychiatric (risk) mechanisms and theoretical predictions in prefrontal cortex (PFC) and hippocampus (HC) neurons and networks, relying mainly on genetic animal models for psychiatric diseases. In these, we performed electrophysiological recordings of groups of individual neurons. To this end, we built and tested two electrophysiological setups. The first was for in-vivo measurements in anesthetized and head-fixed awake animals, allowing for the recording of up to 128 extracellular channels combined with whole-cell patch clamp recordings. The second setup was devised for behavioral experiments under concurrent electrophysiological control. It therefore comprises a custom-built automated eight-arm radial maze, which is being used for various spatial working memory tasks. Additionally, the setup allows recording up to 64 channels of extracellular signals (action potentials from individual neurons). Both setups together are being used for complementary in-vivo experiments in PFC and HC.
We initially probed three genetic animal models for this project: mice which lacked a membrane-based calcium channel (CaV1.2 or CaV1.3 knockout, respectively), mice with the microdeletion (MD) 15q13, and rats overexpressing micro-RNA (miRNA) 137. In acute brain slice preparations, PFC neurons of CaV1.2 and CaV1.3 knockout mice showed electrophysiological properties differing from those of controls (using the model-based approach from B5). MD 15q13 mice lack several genes on chromosome 15, a mutation which in humans leads to a massively increased odds ratio for developing schizophrenia and which codes for, among others, the dopamine degradation protein COMT. Since, however, behavioral tests in CaV1.2/ CaV1.3 and MD 15q13 mice initially appeared inconclusive (but see C8), we focused on the micro-RNA (miR-137) overexpressing transgenic rat which became available recently. Here, in cognitive tests performed in our 8-arms radial maze, we found working memory impairments. Electrophysiological assessment of this animal model in combination with cognitive behavioral tests is being continued at the CIMH and will lead to a better understanding of the pathomechanisms of schizophrenia.
In addition to genetic animal models, we also examined critical brain maturation processes in wild-type animals. Disturbances of brain maturation due to environmental effects (e. g. cannabis consumption or poisonous substances) are thought to be major risk factors for numerous psychiatric conditions. With respect to disruptions of brain maturation processes in early postnatal stadiums, we successfully implemented an age-dependent numerical computer model based on in vitro experimental results (adaptive exponential LIF neurons; in collaboration with Dr. Joachim Hass, project B5). Work is being continued using these models to better understand our in vivo data of single cell activity. In a further step, we will use these models to explain early deviations of the postnatal development of neuronal networks in animal models for psychiatric disorders.
Concerning another field of psychiatrically relevant systems mechanisms, we found an interesting mechanism involved in memory consolidation during sleep: In the entorhinal cortex (EC), we found a subgroup of neurons which, upon receiving input from other parts of the cerebrum, stay continuously active (dubbed “persistent activity”). Considering that cell death in entorhinal cortex is one of the first pathophysiological processes in the early Alzheimers disease, this phenomenon might have a big impact on memory formation and can be readily examined experimentally (Hahn et al., 2012; McFarland et al., 2011). In summary, we established behavioral physiology paradigms which allow experimental examination of relationships between genes/neuronal activity and psychiatrically relevant behavior.

Participating groups:

Key publications:

Hahn TT, McFarland JM, Berberich S, Sakmann B, Mehta MR (2012) Spontaneous persistent activity in entorhinal cortex modulates cortico-hippocampal interaction in vivo. Nat Neurosci. 15(11):1531-8 .
McFarland JM, Hahn TT, Mehta MR (2011) Explicit-duration hidden Markov model inference of UP-DOWN states from continuous signals. PLoS One 6(6):e21606 .