Preserved Calretinin Interneurons in an App Model of Alzheimer’s Disease Disrupt Hippocampal Inhibition via Upregulated P2Y1 Purinoreceptors
| Autor: | Afia Ali, Jiachen Shi, Alexandra L. Petrache, Anqi Shi |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
Male
Cognitive Neuroscience Glutamate decarboxylase Hippocampal formation Inhibitory postsynaptic potential 03 medical and health sciences Cellular and Molecular Neuroscience Amyloid beta-Protein Precursor Receptors Purinergic P2Y1 0302 clinical medicine Downregulation and upregulation synapse Alzheimer Disease Animals Gene Knock-In Techniques CA1 Region Hippocampal Neuroinflammation 030304 developmental biology 0303 health sciences Amyloid beta-Peptides interneurons Chemistry astrocytes Neural Inhibition Up-Regulation Mice Inbred C57BL Disease Models Animal nervous system Calbindin 2 Excitatory postsynaptic potential P2Y1 receptors Original Article Calretinin Neuroscience Alzheimer’s disease 030217 neurology & neurosurgery Homeostasis |
| Zdroj: | Cerebral Cortex (New York, NY) |
| ISSN: | 1460-2199 1047-3211 |
| Popis: | To understand the pathogenesis of specific neuronal circuit dysfunction in Alzheimer’s disease (AD), we investigated the fate of three subclasses of “modulatory interneurons” in hippocampal CA1 using the AppNL-F/NL-F knock-in mouse model of AD. Cholecystokinin- and somatostatin-expressing interneurons were aberrantly hyperactive preceding the presence of the typical AD hallmarks: neuroinflammation and amyloid-β (Aβ) accumulation. These interneurons showed an age-dependent vulnerability to Aβ penetration and a reduction in density and coexpression of the inhibitory neurotransmitter GABA synthesis enzyme, glutamic acid decarboxylase 67 (GAD67), suggesting a loss in their inhibitory function. However, calretinin (CR) interneurons—specialized to govern only inhibition, showed resilience to Aβ accumulation, preservation of structure, and displayed synaptic hyperinhibition, despite the lack of inhibitory control of CA1 excitatory pyramidal cells from midstages of the disease. This aberrant inhibitory homeostasis observed in CA1 CR cells and pyramidal cells was “normalized” by blocking P2Y1 purinoreceptors, which were “upregulated” and strongly expressed in CR cells and astrocytes in AppNL-F/NL-F mice in the later stages of AD. In summary, AD-associated cell-type selective destruction of inhibitory interneurons and disrupted inhibitory homeostasis rectified by modulation of the upregulated purinoreceptor system may serve as a novel therapeutic strategy to normalize selective dysfunctional synaptic homeostasis during pathogenesis of AD. |
| Databáze: | OpenAIRE |
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