Proceedings of The Physiological Society
University of Oxford (2011) Proc Physiol Soc 23, PC51
Neuronal over-expression of Neuregulin-1 slows carbachol-induced gamma oscillations and alters GABAergic inhibition in hippocampus
W. Nissen1, P. J. Harrison2, O. Paulsen3, K. Lamsa1
1. Pharmacology, University of Oxford, Oxford, United Kingdom. 2. Psychiatry, University of Oxford, Oxford, United Kingdom. 3. Physiology, Development and Neuroscience, University of Cambridge, Cambridge, United Kingdom.
The neuronal growth factor Neuregulin 1 (NRG1) and its receptor ErbB4 are involved in neurodevelopment and postnatal synaptic maturation. Behavioural phenotyping of transgenic mice that over-express type I isoform of NRG1 (NRG1tyI) under the Thy1 promoter (1) has revealed an age-emergent impairment of hippocampal-dependent spatial working memory. The underlying neurobiological changes are unclear and we therefore studied the role of increased NRG1tyI expression on hippocampal network functioning in the transgenic mice (1-6 months old). We discovered changes in carbachol-induced hippocampal gamma oscillations (20-80 Hz) and in the rhythmic GABAergic inhibition that entrains CA3 pyramidal cells to the gamma rhythm. Recordings were made from 350-400µm thick acute hippocampal slices, prepared from mice terminally anaesthetised with pentobarbitone sodium (dosage ~0.2mg/g, i.p.). Gamma oscillations were induced by application of 5-20µM carbachol. The peak frequency, but not the power, of oscillations in the CA3 area was significantly reduced in transgenic mice (mean frequency ± SEM: 22.1±0.5 Hz, n=34 slices) compared to wild-type littermates (26.4±0.5 Hz, n=46 slices, Mann-Whitney U Test, p<0.001). Action potential firing of CA3 principal cells was similarly phase-locked to the field potential gamma cycles in both genotypes. However, the dynamics of inhibitory synaptic currents in CA3 pyramidal cells during the gamma oscillation were sustained in the NRG1tyI mice compared to wild type littermates (half amplitude decay time in NRG1tyI: 12.5±0.5 ms, n=8 cells vs wt: 10.3±0.2 ms, n=13 cells, independent sample T test, p<0.001). In contrast, excitatory current kinetics were not altered. These findings suggest that the local inhibitory GABAergic circuits responsible for the rhythmic inhibition are changed in the mice over-expressing NRG1. Because Parvalbumin-positive (PV+) interneurons are crucial for both working memory (2) as well as gamma oscillations (3), and are a likely primary target of NRG1 signalling (4), we selectively study PV+ interneuron-mediated inhibition in the CA3 circuit. We used optical stimulation of light-gated channelrhodopsin-2 (ChR2) selectively expressed by PV+ axons: NRG1tyI mice crossbred with PV-Cre mice were exposed to inhalation anaesthesia with isoflurane (induction 4%, maintenance 1.5 -2% in O2) and injected with adeno-associated virus encoding floxed ChR2-YFP (yellow fluorescent protein) under stereotaxic guidance. Following in vivo expression of the viral vector for 10-21 days, recordings were made in acute hippocampal slices. Using this approach, we aim to uncover mechanisms underlying altered inhibitory signalling onto pyramidal cells in NRG1tyI transgenic mice.
Where applicable, experiments conform with Society ethical requirements