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Molecular mechanisms of activity dependent survival in the adult EC

ABSTRACT: Entorhinal cortex layer II (ECII) neurons are some of the first cells to degenerate in Alzheimer’s Disease. Losing this region is impactful for cognition as ECII projections form the major cortical input into the hippocampus. To dissect the behavioral impact of ECII loss on hippocampal function, the Jankowsky lab created a chemogenetic mouse model in which ECII neurons express an engineered chloride channel (GlyCl) that prevents neuronal firing upon binding a systemically-delivered ligand. Using this model, we unexpectedly discovered that ECII neurons are particularly vulnerable to silencing and may require activity for survival. This study aims to determine the transcriptional changes correlating to degenerative phenotypes observed after electrical silencing of adult entorhinal cortex neurons.

ORGANISM(S): Mus musculus

PROVIDER: GSE255676 | GEO | 2025/12/04

REPOSITORIES: GEO

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Project description:Sanfilippo syndrome type B (MPS III B) is an autosomal recessive, neurodegenerative disease of children, characterized by profound mental retardation and dementia. The primary cause is mutation in the NAGLU gene, resulting in deficiency of N-acetylglucosaminidase and lysosomal accumulation of heparan sulfate. In the mouse model of MPS III B, neurons and microglia display the characteristic vacuolation of lysosomal storage of undegraded substrate, but neurons in the medial entorhinal cortex (MEC) display accumulation of several additional substances. We used whole genome microarray analysis to examine differential gene expression in MEC neurons isolated by laser capture microdissection from Naglu -/- and Naglu +/- mice. Neurons from the lateral entorhinal cortex (LEC) were used as tissue controls. The highest increase in gene expression (6- to 7-fold between mutant and control) in MEC and LEC neurons was that of Lyzs, which encodes lysozyme, but accumulation of lysozyme protein was seen in MEC neurons only. Because of a report that lysozyme induced the formation of hyperphosphorylated tau (P-tau) in cultured neurons, we searched for P-tau by immunohistochemistry. P-tau was found in MEC of Naglu -/- mice, in the same neurons as lysozyme. In older mutant mice, it was also seen in the dentate gyrus, an area important for memory. Electron microscopy of dentate gyrus neurons showed cytoplasmic inclusions of paired helical filaments - P-tau aggregates characteristic of tauopathies, a group of age-related dementias that includes Alzheimer disease. Our findings indicate that the Sanfilippo syndrome type B should also be considered a tauopathy. Two-condition experiment, Naglu-/- (affected) vs. Naglu+/- (unaffected control) of neurons from two adjacent brain regions: medial entorhinal cortex (MEC) and lateral entorhinal cortex (LEC). Biological replicates: 3 MEC Naglu-/-, 3 MEC Naglu+/-, 3 LEC Naglu-/- and 3 LEC Naglu+/-. Comparisons were made between 3 pairs of mutant and control female littermates for MEC and LEC neurons with dye switch duplicates, for a total of 12 microarrays.

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Molecular mechanisms of activity dependent survival in the adult EC

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