Summary Central regulation of metabolic physiology is mediated critically through neuronal functions; however, if astrocytes are also essential remains unclear. Here we show that the high-order processes of astrocytes in the mediobasal hypothalamus displayed shortening in fasting while elongation in fed status. Chronic overnutrition and astrocytic IKKβ/NF-κB upregulation similarly impaired astrocytic plasticity leading to sustained shortening of high-order processes. In physiology, astrocytic IKKβ/NF-κB upregulation resulted in early-onset effects including glucose intolerance and blood pressure rise and late-onset effects including body weight and fat gain. Appropriate inhibition in astrocytic IKKβ/NF-κB protected against chronic overnutrition from impairing astrocytic plasticity and these physiological functions. Mechanistically, astrocytic regulation of hypothalamic extracellular GABA level and therefore BDNF expression were found partly accountable. Hence, astrocytic process plasticity and IKKβ/NF-κB play significant roles in central control of blood glucose, blood pressure and body weight as well as the central induction of these physiological disorders leading to disease.

GABAergic interneurons are essential for a functional equilibrium between excitatory and inhibitory impulses throughout the CNS. Disruption of this equilibrium can lead to various neurological or neuropsychiatric disorders such as epilepsy or schizophrenia. Schizophrenia itself is clinically defined by negative (e.g., depression) and positive (e.g., hallucinations) symptoms as well as cognitive dysfunction. GABAergic interneurons are proposed to play a central role in the etiology and progression of schizophrenia; however, the specific mechanisms and the time-line of symptom development as well as the distinct involvement of cortical and hippocampal GABAergic interneurons in the etiology of schizophrenia-related symptoms are still not conclusively resolved. Previous work demonstrated that GABAergic interneurons can be selectively depleted in adult mice by means of saporin-conjugated anti-vesicular GABA transporter antibodies (SAVAs) in vitro and in vivo. Given their involvement in schizophrenia-related disease etiology, we ablated GABAergic interneurons in the medial prefrontal cortex (mPFC) and dorsal hippocampus (dHPC) in adult male C57BL/6N mice. Subsequently we assessed alterations in anxiety, sensory processing, hyperactivity and cognition after long-term (>14 days) and short-term (<14 days) GABAergic depletion. Long-term GABAergic depletion in the mPFC resulted in a decrease in sensorimotor-gating and impairments in cognitive flexibility. Notably, the same treatment at the level of the dHPC completely abolished spatial learning capabilities. Short-term GABAergic depletion in the dHPC revealed a transient hyperactive phenotype as well as marked impairments regarding the acquisition of a spatial memory. In contrast, recall of a spatial memory was not affected by the same intervention. These findings emphasize the importance of functional local GABAergic networks for the encoding but not the recall of hippocampus-dependent spatial memories.

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Even in the absence of neurodegenerative diseases, progressing age often coincides with cognitive decline and morphological changes. However, longitudinal studies that directly link these two processes are missing. In this proof-of-concept study we therefore performed repeated within-subject testing of healthy male R26R mice in a spatial learning task in combination with manganese-enhanced volumetric MRI analyses at the ages of 8, 16, and 24 months. We grouped the mice into good and poor performers (n = 6, each), based on their spatial learning abilities at the age of 24 months. Using this stratification, we failed to detect a priori volume differences, but observed a significant decrease in total hippocampal volume over time for both groups. Interestingly, this volume decrease was specific for the dorsal hippocampus and significantly accelerated in poor performers between 16 and 24 months of age. This is the first time that individual changes in hippocampal volume were traced alongside cognitive performance within the same subjects over 1½ years. Our study points to a causal link between volume loss of the dorsal hippocampus and cognitive impairments. In addition, it suggests accelerated degenerative processes rather than a priori volume differences as determining trajectories of age-related cognitive decline. Despite the relatively small sample sizes, the strong behavioral and moderate morphological alterations demonstrate the general feasibility of longitudinal studies of age-related decline in cognition and hippocampus integrity. © 2016 Wiley Periodicals, Inc.

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Expression of the lacZ-sequence is a widely used reporter-tool to assess the transgenic and/or transfection efficacy of a target gene in mice. Once activated, lacZ is permanently expressed. However, protein accumulation is one of the hallmarks of neurodegenerative diseases. Furthermore, the protein product of the bacterial lacZ gene is ß-galactosidase, an analog to the mammalian senescence-associated ß-galactosidase, a molecular marker for aging. Therefore we studied the behavioral, structural and molecular consequences of lacZ expression in distinct neuronal sub-populations. lacZ expression in cortical glutamatergic neurons resulted in severe impairments in hippocampus-dependent memory accompanied by marked structural alterations throughout the CNS. In contrast, GFP expression or the expression of the ChR2/YFP fusion product in the same cell populations did not result in either cognitive or structural deficits. GABAergic lacZ expression caused significantly decreased hyper-arousal and mild cognitive deficits. Attenuated structural and behavioral consequences of lacZ expression could also be induced in adulthood, and lacZ transfection in neuronal cell cultures significantly decreased their viability. Our findings provide a strong caveat against the use of lacZ reporter mice for phenotyping studies and point to a particular sensitivity of the hippocampus formation to detrimental consequences of lacZ expression. © 2016 Wiley Periodicals, Inc.