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Impaired parvalbumin interneurons in the retrosplenial cortex as the cause of sex-dependent vulnerability in Alzheimer’s disease [Xenium]

ABSTRACT: Alzheimer’s disease is a debilitating neurodegenerative disorder with no cure and few treatment options. In early stages of Alzheimer’s disease, impaired metabolism and functional connectivity of the retrosplenial cortex strongly predict future cognitive impairments. Therefore, understanding Alzheimer’s disease-related deficits in the retrosplenial cortex is critical for understanding the origins of cognitive impairment and identifying early treatment targets. Using the 5xFAD mouse model, we discovered early, sex-dependent alterations in parvalbumin-interneuron transcriptomic profiles. This corresponded with impaired parvalbumin-interneuron activity, which was sufficient to induce cognitive impairments and dysregulate retrosplenial functional connectivity. In fMRI scans from patients with mild cognitive impairment and Alzheimer’s disease, we observed a similar sex-dependent dysregulation of retrosplenial cortex functional connectivity and, in post-mortem tissue from subjects with Alzheimer’s disease, a loss of parvalbumin interneurons. Reversal of cognitive deficits by stimulation of parvalbumin interneurons in the retrosplenial cortex suggests that this may serve as a promising novel therapeutic strategy.

ORGANISM(S): Mus musculus

PROVIDER: GSE277463 | GEO | 2025/04/13

REPOSITORIES: GEO

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Impaired parvalbumin interneurons in the retrosplenial cortex as the cause of sex-dependent vulnerability in Alzheimer’s disease [GeoMx]

Project description:Alzheimer’s disease is a debilitating neurodegenerative disorder with no cure and few treatment options. In early stages of Alzheimer’s disease, impaired metabolism and functional connectivity of the retrosplenial cortex strongly predict future cognitive impairments. Therefore, understanding Alzheimer’s disease-related deficits in the retrosplenial cortex is critical for understanding the origins of cognitive impairment and identifying early treatment targets. Using the 5xFAD mouse model, we discovered early, sex-dependent alterations in parvalbumin-interneuron transcriptomic profiles. This corresponded with impaired parvalbumin-interneuron activity, which was sufficient to induce cognitive impairments and dysregulate retrosplenial functional connectivity. In fMRI scans from patients with mild cognitive impairment and Alzheimer’s disease, we observed a similar sex-dependent dysregulation of retrosplenial cortex functional connectivity and, in post-mortem tissue from subjects with Alzheimer’s disease, a loss of parvalbumin interneurons. Reversal of cognitive deficits by stimulation of parvalbumin interneurons in the retrosplenial cortex suggests that this may serve as a promising novel therapeutic strategy.

2025-04-13 | GSE277793 | GEO

Rbfox1 mediates cell-type specific splicing in cortical interneurons

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Impaired parvalbumin interneurons in the retrosplenial cortex as the cause of sex-dependent vulnerability in Alzheimer’s disease [GeoMx]

Project description:Impaired parvalbumin interneurons in the retrosplenial cortex as the cause of sex-dependent vulnerability in Alzheimer’s disease [GeoMx]

| PRJNA1164202 | ENA

Impaired parvalbumin interneurons in the retrosplenial cortex as the cause of sex-dependent vulnerability in Alzheimer’s disease [Xenium]

Project description:Impaired parvalbumin interneurons in the retrosplenial cortex as the cause of sex-dependent vulnerability in Alzheimer’s disease [Xenium]

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Distinct molecular programs regulate synapse specificity in cortical inhibitory circuits

Project description:How neuronal connections are established and organized in functional networks determines brain function. In the mouse cerebral cortex, different classes of GABAergic interneurons exhibit specific connectivity patterns that underlie their ability to shape temporal dynamics and information processing. Much progress has been made parsing interneuron diversity, yet the molecular mechanisms by which interneuron subtype-specific connectivity motifs emerge remain unclear. Here we investigate transcriptional dynamics in different classes of interneurons during the formation of cortical inhibitory circuits. We found that whether the interneurons synapse with pyramidal neurons on their dendrites, soma, or axon initial segment is determined by synaptic molecules that are expressed in a subtype-specific manner. Thus cell-specific molecular programs that unfold during early postnatal development underlie the connectivity patterns of cortical interneurons.

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DOT1L deletion impairs the development of cortical Parvalbumin-expressing interneurons

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Cortical region confers neuron-type-specific vulnerability to human APP expression

Project description:Alzheimer’s Disease is a devastating and an irreversible neurodegenerative disease currently afflicting 50 million individuals worldwide, a number expected to escalate three-fold over the next 25 years. Preventative treatment is of dire importance, and yet, cellular mechanisms underlying early regional vulnerability in Alzheimer’s Disease remain unknown. In human patients with Alzheimer’s Disease, the earliest observed pathophysiological correlate to cognitive decline is hyperexcitability. In mouse models, early hyperexcitability has been shown in the cortical region first impacted by Alzheimer’s Disease. The origin of hyperexcitability in early stage-disease and why it preferentially emerges in specific regions is unclear. Using cortical-region and cell-type- specific proteomics and patch-clamp electrophysiology, we uncovered differential susceptibility to human-specific APP in a model of sporadic Alzheimer’s Disease. Shockingly, our findings reveal that early entorhinal hyperexcitability may result from intrinsic vulnerability of parvalbumin interneurons, prior to changes in surrounding excitatory neurons. This study suggests early disease interventions addressing non-excitatory cell-types may protect regions first vulnerable to pathological symptoms of Alzheimer’s Disease and downstream cognitive decline.

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Sonic hedgehog Activation Restores Interneurons and Cognitive Function in Newborns with Intraventricular Hemorrhage

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Pyramidal neurons proportionately alter the identity and survival of specific cortical interneuron subtypes

Project description:The mammalian cerebral cortex comprises a complex neuronal network that maintains a delicate balance between excitatory neurons and inhibitory interneurons. Previous studies, including our own research, have shown that specific interneuron subtypes are closely associated with particular pyramidal neuron types, forming stereotyped local inhibitory microcircuits. However, the developmental processes that establish these precise networks are not well understood. Here we show that pyramidal neuron types are instrumental in maintaining the terminal differentiation and survival of specific associated interneuron subtypes. In a wild-type cortex, the relative abundance of different interneuron subtypes aligns precisely with the pyramidal neuron types with which they synaptically target. In Fezf2 mutant cortex, characterized by the absence of layer 5 pyramidal tract neurons and an expansion of layer 6 intratelencephalic neurons, we observed a corresponding decrease in associated layer 5b interneurons and an increase in layer 6 subtypes. Interestingly, these shifts in composition are achieved through mechanisms that are specific to different interneuron types. While SST interneurons adjust their abundance to the change in pyramidal neuron prevalence through the regulation of programmed cell death, parvalbumin cells alter their identity. These findings illustrate two key strategies by which the dynamic interplay between pyramidal neurons and interneurons allows local microcircuits to be sculpted precisely. These insights underscored the precise roles of extrinsic signals from pyramidal cells in the establishment of interneuron diversity and their subsequent integration into local cortical microcircuits.

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Gene expression of L3 parvalbumin neurons in the DLPFC comparing schizophrenia with unaffected subjects

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