1. Early alterations in hippocampal perisomatic GABAergic synapses and network oscillations in a mouse model of Alzheimer's disease amyloidosis.
- Author
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Hollnagel JO, Elzoheiry S, Gorgas K, Kins S, Beretta CA, Kirsch J, Kuhse J, Kann O, and Kiss E
- Subjects
- Action Potentials, Alzheimer Disease genetics, Alzheimer Disease pathology, Amyloid beta-Protein Precursor genetics, Amyloidosis genetics, Amyloidosis pathology, Animals, CA1 Region, Hippocampal metabolism, CA1 Region, Hippocampal pathology, CA3 Region, Hippocampal metabolism, CA3 Region, Hippocampal pathology, Disease Models, Animal, GABAergic Neurons metabolism, GABAergic Neurons pathology, Gamma Rhythm, Hippocampus pathology, Humans, In Vitro Techniques, Interneurons metabolism, Interneurons pathology, Male, Mice, Mice, Inbred C57BL, Mice, Transgenic, Nerve Net metabolism, Nerve Net pathology, Parvalbumins metabolism, Presenilin-1 genetics, Pyramidal Cells metabolism, Pyramidal Cells pathology, Synapses metabolism, Alzheimer Disease metabolism, Amyloidosis metabolism, Hippocampus metabolism
- Abstract
Several lines of evidence imply changes in inhibitory interneuron connectivity and subsequent alterations in oscillatory network activities in the pathogenesis of Alzheimer's Disease (AD). Recently, we provided evidence for an increased immunoreactivity of both the postsynaptic scaffold protein gephyrin and the GABAA receptor γ2-subunit in the hippocampus of young (1 and 3 months of age), APPPS1 mice. These mice represent a well-established model of cerebral amyloidosis, which is a hallmark of human AD. In this study, we demonstrate a robust increase of parvalbumin immunoreactivity and accentuated projections of parvalbumin positive (PV+) interneurons, which target perisomatic regions of pyramidal cells within the hippocampal subregions CA1 and CA3 of 3-month-old APPPS1 mice. Colocalisation studies confirmed a significant increase in the density of PV+ projections labeled with antibodies against a presynaptic (vesicular GABA transporter) and a postsynaptic marker (gephyrin) of inhibitory synapses within the pyramidal cell layer of CA1 and CA3. As perisomatic inhibition by PV+-interneurons is crucial for the generation of hippocampal network oscillations involved in spatial processing, learning and memory formation we investigated the impact of the putative enhanced perisomatic inhibition on two types of fast neuronal network oscillations in acute hippocampal slices: 1. spontaneously occurring sharp wave-ripple complexes (SPW-R), and 2. cholinergic γ-oscillations. Interestingly, both network patterns were generally preserved in APPPS1 mice similar to WT mice. However, the comparison of simultaneous CA3 and CA1 recordings revealed that the incidence and amplitude of SPW-Rs were significantly lower in CA1 vs CA3 in APPPS1 slices, whereas the power of γ-oscillations was significantly higher in CA3 vs CA1 in WT-slices indicating an impaired communication between the CA3 and CA1 network activities in APPPS1 mice. Taken together, our data demonstrate an increased GABAergic synaptic output of PV+ interneurons impinging on pyramidal cells of CA1 and CA3, which might limit the coordinated cross-talk between these two hippocampal areas in young APPPS1 mice and mediate long-term changes in synaptic inhibition during progression of amyloidosis., Competing Interests: The authors have declared that no competing interests exist.
- Published
- 2019
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