Menin Deficiency Leads to Depressive-like Behaviors in Mice by Modulating Astrocyte-Mediated Neuroinflammation

Area of Science:

• Neuroscience
• Molecular Biology
• Psychiatry

Background:

• Astrocyte dysfunction and neuroinflammation are implicated in major depressive disorder (MDD) pathogenesis.
• The precise molecular mechanisms linking astrocytes to MDD remain largely elusive.

Purpose of the Study:

• To investigate the role of multiple endocrine neoplasia type 1 (Men1) and its protein product, menin, in astrocyte function and its contribution to MDD.
• To elucidate the molecular pathways through which menin deficiency in astrocytes influences neuroinflammation and depressive-like behaviors.

Main Methods:

• Utilized mouse models exposed to chronic unpredictable mild stress (CUMS) and lipopolysaccharide to assess Men1 expression.
• Generated astrocyte-specific Men1 knockout (GcKO) mice to study the impact of menin deficiency in astrocytes.
• Investigated NF-κB activation, IL-1β production, and depressive-like behaviors in GcKO mice.
• Administered NF-κB inhibitors and IL-1β receptor antagonists to assess their effects on depressive behaviors.
• Analyzed human subjects for single nucleotide polymorphisms (SNPs) in the MEN1 gene associated with MDD risk.

Main Results:

• Menin expression was reduced in the brains of mice under stress conditions (CUMS, LPS).
• Astrocyte-specific reduction of menin (GcKO mice) induced depressive-like behaviors.
• Menin deficiency in astrocytes led to increased NF-κB activation and IL-1β production.
• Depressive-like behaviors in GcKO mice were ameliorated by NF-κB inhibition or IL-1β receptor antagonism.
• A human SNP (rs375804228) in MEN1, causing G503D substitution, was associated with increased MDD risk.
• The G503D substitution disrupted menin-p65 interaction, enhancing NF-κB activation and IL-1β production.

Conclusions:

• Menin plays a critical role in regulating neuroinflammation within astrocytes.
• Menin deficiency in astrocytes contributes to depressive-like behaviors through the NF-κB/IL-1β pathway.
• Menin represents a potential therapeutic target for major depressive disorder.