Increased GHS-R1a expression in the hippocampus impairs memory encoding and contributes to AD-associated memory...

Area of Science:

• Neuroscience
• Molecular Biology
• Neurodegenerative Diseases

Background:

• The ghrelin receptor (GHS-R1a) is a key regulator of metabolism and nutrient sensing.
• Elevated GHS-R1a expression is found in the hippocampus of Alzheimer's disease (AD) patients and models.
• The direct impact of hippocampal GHS-R1a on AD-associated memory deficits is not fully understood.

Purpose of the Study:

• To investigate the causal role of increased GHS-R1a expression in hippocampal neurons on memory formation.
• To explore the therapeutic potential of targeting GHS-R1a in AD models.

Main Methods:

• Manipulated GHS-R1a expression in dCA1 pyramidal neurons of mice.
• Administered LEAP2, an endogenous GHS-R1a antagonist.
• Utilized chemogenetics to modulate neuronal activity.
• Assessed hippocampus-dependent memory and spatial memory encoding.
• Examined GHS-R1a deletion in APP/PS1 AD model mice.

Main Results:

• Increased GHS-R1a in dCA1 neurons impaired memory formation and reduced neuronal excitability.
• LEAP2 administration and chemogenetic activation of GHS-R1a neurons rescued memory deficits.
• Elevated GHS-R1a hampered spatial memory encoding and reduced neuronal engram size.
• GHS-R1a deletion ameliorated memory deficits in APP/PS1 mice.

Conclusions:

• Hippocampal GHS-R1a has a negative causal effect on memory encoding.
• Blocking aberrant GHS-R1a activity presents a potential therapeutic strategy for AD cognitive decline.