Heart-type fatty acid binding protein regulates dopamine D2 receptor function in mouse brain

Area of Science:

• Neuroscience
• Molecular Biology
• Biochemistry

Background:

• Fatty acid binding proteins (FABPs) are crucial for cellular energy and signaling.
• Heart-type fatty acid binding protein (H-FABP, FABP3) is abundant in mature brain neurons, involved in fatty acid metabolism.
• The specific role of H-FABP in brain function, particularly its interaction with neurotransmitter systems, remains largely undefined.

Purpose of the Study:

• To investigate the precise function of H-FABP in the brain.
• To elucidate the interaction between H-FABP and the dopamine D2 receptor (D2R).
• To determine the impact of H-FABP deficiency on dopaminergic and cholinergic signaling pathways in the striatum.

Main Methods:

• Confirmation of H-FABP binding to D2R in brain extracts using co-immunoprecipitation.
• Immunohistochemical analysis to determine H-FABP and D2R colocalization in the mouse dorsal striatum.
• Behavioral analysis of H-FABP knockout (KO) mice in response to psychostimulants and antipsychotics.
• Measurement of neurotransmitter release (acetylcholine and glutamate) and protein phosphorylation (CaMKII, ERK) in H-FABP KO mouse striatum.
• In vitro studies using H-FABP-overexpressing neuroblastoma cells to assess D2R-mediated signaling.

Main Results:

• H-FABP directly binds to D2R and colocalizes with it in the dorsal striatum.
• H-FABP is localized in cholinergic interneurons and glutamatergic terminals, but not in dopamine terminals.
• H-FABP KO mice exhibit altered responses to methamphetamine and haloperidol, indicating D2R dysfunction.
• Aberrant increases in acetylcholine and glutamate release, along with elevated CaMKII and ERK phosphorylation, were observed in H-FABP KO mice striatum.
• Elevated ERK phosphorylation was confirmed in H-FABP-overexpressing cells upon D2R stimulation.

Conclusions:

• H-FABP plays a significant role in regulating D2R function within the striatum.
• H-FABP expression in specific neuronal populations (cholinergic interneurons, glutamatergic terminals) is critical for normal dopaminergic signaling.
• H-FABP deficiency leads to dysregulation of neurotransmitter release and downstream signaling pathways, impacting brain function.