Mitochondria contribute to shape intraneuronal Ca 2+ signals. Excessive Ca 2+ taken up by mitochondria could lead to cell death. Amyloid beta (Aβ) causes cytosolic Ca 2+ overload, but the effects of Aβ on mitochondrial Ca 2+ levels in Alzheimer's disease (AD) remain unclear. Using a ratiometric Ca 2+ indicator targeted to neuronal mitochondria and intravital multiphoton microscopy, we find increased mitochondrial Ca 2+ levels associated with plaque deposition and neuronal death in a transgenic mouse model of cerebral β-amyloidosis. Naturally secreted soluble Aβ applied onto the healthy brain increases Ca 2+ concentration in mitochondria, which is prevented by blockage of the mitochondrial calcium uniporter. RNAsequencing from post-mortem AD human brains shows downregulation in the expression of mitochondrial influx Ca 2+ transporter genes, but upregulation in the genes related to mitochondrial Ca 2+ efflux pathways, suggesting a counteracting effect to avoid Ca 2+ overload. We propose lowering neuronal mitochondrial Ca 2+ by inhibiting the mitochondrial Ca 2+ uniporter as a novel potential therapeutic target against AD.
Fear is adaptive when the level of the response rapidly scales to degree of threat. Using a discrimination procedure consisting of danger, uncertainty, and safety cues, we have found rapid fear scaling (within 2 s of cue presentation) in male rats. Here, we examined a possible role for the nucleus accumbens core (NAcc) in the acquisition and expression of fear scaling. In experiment 1, male Long-Evans rats received bilateral sham or neurotoxic NAcc lesions, recovered, and underwent fear discrimination. NAcc-lesioned rats were generally impaired in scaling fear to degree of threat, and specifically impaired in rapid uncertainty-safety discrimination. In experiment 2, male Long-Evans rats received NAcc transduction with halorhodopsin (Halo) or a control fluorophore. After fear scaling was established, the NAcc was illuminated during cue or control periods. NAcc-Halo rats receiving cue illumination were specifically impaired in rapid uncertainty-safety discrimination. The results reveal a general role for the NAcc in scaling fear to degree of threat, and a specific role in rapid discrimination of uncertain threat and safety.
Alzheimer’s disease (AD) is characterized by progressive memory loss and cognitive decline. These impairments correlate with early alterations in neuronal network activity in AD patients. Disruptions in the activity of individual neurons have been reported in mouse models of amyloidosis. However, the impact of amyloid pathology on the spontaneous activity of distinct neuronal types remains unexplored in vivo. Here we use in vivo calcium imaging with multiphoton microscopy to monitor and compare the activity of excitatory and two types of inhibitory interneurons in the cortices of APP/PS1 and control mice under isoflurane anesthesia. We also determine the relationship between amyloid accumulation and the deficits in spontaneous activity in APP/PS1 mice. We show that somatostatin-expressing (SOM) interneurons are hyperactive, while parvalbumin-expressing interneurons are hypoactive in APP/PS1 mice. Only SOM interneuron hyperactivity correlated with proximity to amyloid plaque. These inhibitory deficits were accompanied by decreased excitatory neuron activity in APP/PS1 mice. Our study identifies cell-specific neuronal firing deficits in APP/PS1 mice driven by amyloid pathology. These findings highlight the importance of addressing the complexity of neuron-specific deficits to ameliorate circuit dysfunction in Alzheimer’s disease.
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