GABAergic interneurons in a Disc1-Mouse model for depression - Influence on neuronal network activity in the prefrontal cortex and behaviour
Human Cognitive and Systems Neuroscience
Final Report Abstract
Disrupted-in-schizophrenia-1 (Disc1) is a gene mutation, which has been identified in humans suffering from psychiatric disorders including depression and schizophrenia. A series of investigations points to the critical role of GABAergic inhibitory interneurons (INs) in the emergence of cognitive dysfunction in psychiatric illnesses. Among the various neocortical INT types, especially fast-spiking parvalbumin-expressing interneurons (PVIs) have attracted substantial attention. They are involved in the generation of fast brain rhythms at gamma (30-100 Hz) frequencies, which are believed to underlie the processing and encoding of information. Indeed, individuals with depression or schizophrenia show disturbed gamma (30-150 Hz) activity patterns. The underlying network defects remained, however, largely unknown. In our previously published work we showed using a systems-biological approach that gamma synchrony in the medial prefrontal cortex (mPFC) PFC of Disc1 mutant mice is markedly reduced. This reduction was correlated with a diminished number of (PVIs), a ~60% reduced synaptic transmission at their GABAergic output synapses and a reduced excitatory drive onto PVIs. In spite of these impressive changes, it remained unclear how changes in PVI input and output function may influence neuronal population activity. In the second study, we aimed to address this fundamental question by combining in vivo electrophysiological and optophysiological investigations with viral tools and behavioral analysis. (1) We crossed Disc1 mutant mice with PV-Cre animals (PV-Cre-Disc1-mice) and stereotaxically injected adeno-associated viruses encoding channelrhodopsin-2 (ChR2) and the red fluorophore tdTomato (tdT) flanked by double-inverted loxP sites (AAV-Flex-ChR2-tdT) into the mPFC of PV-Cre-Disc1-mice sensitive to blue light and allowed optogenetic identification of PVIs by brief laser pulses during single-unit recordings. (2) We show that fast-spiking INs including optophysiologically identified PVIs in freely moving mice express reduced average firing rates and lower phase coupling to ongoing gamma oscillations. (3) Spike transmission efficacy at local principal cell (PC)-IN/PVI connections was reduced, suggesting a reduced excitatory effect of local glutamatergic inputs onto fast-spiking INs as a potential underlying mechanism of the observed lower IN rates. (4) Whole-cell patch clamp recordings in acute slice preparations revealed that the kinetic properties of glutamatergic inputs onto PVIs (rise time and decay time constant) was not altered. Moreover, intrinsic membrane properties (e.g. input resistance, discharge pattern) were almost unchanged; however, fast-spiking INs in Disc1 mice expressed reduced levels of dopaminergic D2 receptors, suggesting diminished excitability due to impaired responsiveness to dopamine-mediated excitation. In summary, our data suggest that Disc1 mutation influences the responsiveness of prefrontal fast-spiking INs, including PVIs, to glutamatergic drive via dopaminergic control of IN excitability. A by-product of this study was the unexpected topographic organization in the spatial representation in the mPFC, which is traditionally but in relation to the hippocampus.
Publications
- (2015) Impaired fast-spiking interneuron function in a genetic mouse model of depression. eLife 4
Sauer JF, Strüber M, Bartos M
(See online at https://doi.org/10.7554/eLife.04979) - Recording Spatially Restricted Oscillations in the Hippocampus of Behaving Mice. J Vis Exp 137
Sauer JF, Strüber M, Bartos M (
(See online at https://dx.doi.org/10.3791/57714) - (2019) Enhanced mGlu5 Signaling in Excitatory Neurons Promotes Rapid Antidepressant Effects via AMPA Receptor Activation. Neuron 104:338- 352
Holz A, Mülsch F, Schwarz MK, Hollmann M, Döbrössy MD, Coenen VA, Bartos M, Normann C, Biber K, van Calker D, Serchov T
(See online at https://doi.org/10.1016/j.neuron.2019.07.011) - Topographically organized representation of space and context in the medial prefrontal cortex
Sauer JF, Folschweiller S, Bartos M
(See online at https://doi.org/10.1101/2021.06.04.447085)
