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Abnormal excitability in cortical networks has been reported in patients and animal models of Alzheimer's disease (AD), and other neurodegenerative conditions. Whether hyperexcitability is a core feature of alpha(α)-synucleinopathies, including dementia with Lewy bodies (DLB) is unclear. To assess this, we used two murine models of DLB that express either human mutant α-synuclein (α-syn) the hA30P, or human wild-type α-syn (hWT-α-syn) mice. We observed network hyperexcitability in vitro in young (2–5 months), pre-symptomatic transgenic α-syn mice. Interictal discharges (IIDs) were seen in the extracellular local field potential (LFP) in the hippocampus in hA30P and hWT-α-syn mice following kainate application, while only gamma frequency oscillations occurred in control mice. In addition, the concentration of the GABAA receptor antagonist (gabazine) needed to evoke IIDs was lower in slices from hA30P mice compared to control mice. hA30P mice also showed increased locomotor activity in the open field test compared to control mice. Intracellular recordings from CA3 pyramidal cells showed a more depolarised resting membrane potential in hA30P mice. Quadruple immunohistochemistry for human α-syn, and the mitochondrial markers, porin and the complex IV enzyme cytochrome c oxidase subunit 1 (COX1) in parvalbumin (PV+)-expressing interneurons showed that 25% of PV+ cells contained human α-syn in hA30P mice. While there was no change in PV expression, COX1 expression was significantly increased in PV+ cells in hA30P mice, perhaps reflecting a compensatory change to support PV+ interneuron activity. Our findings suggest that hippocampal network hyperexcitability may be an important early consequence of α-syn-mediated impairment of neuronal/synaptic function, which occurs without any overt loss of PV interneurons. The therapeutic benefit of targeting network excitability early in the disease stage should be explored with respect to α-synucleinopathies such as DLB., Highlights • Young transgenic α-syn mice exhibit network hyperexcitability in the hippocampus in vitro. • Young transgenic α-syn mice have increased locomotor activity in an open field test. • Hippocampal pyramidal cells are more depolarised in young transgenic α-syn mice. • Increased mitochondrial cytochrome c oxidase (complex IV) function in PV+ interneurons in young transgenic a-syn mice.

Chronic inflammation is a common feature of many age‐related conditions including neurodegenerative diseases such as Alzheimer's disease. Cellular senescence is a state of irreversible cell‐cycle arrest, thought to contribute to neurodegenerative diseases partially via induction of a chronic pro‐inflammatory phenotype. In this study, we used a mouse model of genetically enhanced NF‐κB activity (nfκb1 −/−), characterized by low‐grade chronic inflammation and premature aging, to investigate the impact of inflammaging on cognitive decline. We found that during aging, nfkb1 −/− mice show an early onset of memory loss, combined with enhanced neuroinflammation and increased frequency of senescent cells in the hippocampus and cerebellum. Electrophysiological measurements in the hippocampus of nfkb1 −/− mice in vitro revealed deficits in gamma frequency oscillations, which could explain the decline in memory capacity. Importantly, treatment with the nonsteroidal anti‐inflammatory drug (NASID) ibuprofen reduced neuroinflammation and senescent cell burden resulting in significant improvements in cognitive function and gamma frequency oscillations. These data support the hypothesis that chronic inflammation is a causal factor in the cognitive decline observed during aging., Chronic inflammation induces cellular senescence and leads to premature aging and cognitive decline. Anti‐inflammatory treatment reduces neuroinflammation and senescent cell burden, and ameliorates cognitive impairment.

Intracellular accumulation of alpha-synuclein (α-syn) is a key pathological process evident in Lewy body dementias (LBDs), including Parkinson’s disease dementia (PDD) and dementia with Lewy bodies (DLB). LBD results in marked cognitive impairments and changes in cortical networks. To assess the impact of abnormal α-syn expression on cortical network oscillations relevant to cognitive function, we studied changes in fast beta/gamma network oscillations in the hippocampus in a mouse line that over-expresses human mutant α-syn (A30P). We found an age-dependent reduction in the power of the gamma (20–80 Hz) frequency oscillations in slices taken from mice aged 9–16 months (9+A30P), that was not present in either young 2–6 months old (2+A30P) mice, or in control mice at either age. The mitochondrial blockers potassium cyanide and rotenone both reduced network oscillations in a concentration-dependent manner in aged A30P mice and aged control mice but slices from A30P mice showed a greater reduction in the oscillations. Histochemical analysis showed an age-dependent reduction in cytochrome c oxidase (COX) activity, suggesting a mitochondrial dysfunction in the 9+A30P group. A deficit in COX IV expression was confirmed by immunohistochemistry. Overall, our data demonstrate an age-dependent impairment in mitochondrial function and gamma frequency activity associated with the abnormal expression of α-syn. These findings provide mechanistic insights into the consequences of over-expression of α-syn which might contribute to cognitive decline.