Fatty acid binding proteins (FABPs) are essential for energy production and long-chain
polyunsaturated fatty acid-related signaling in the brain and other tissues. Of various FABPs, heart-type
fatty acid binding protein (H-FABP, FABP3) is highly expressed in neurons of mature brain and plays a role in
arachidonic acid incorporation into brain and heart cells. However, the precise function of
H-FABP in brain remains unclear. We previously demonstrated that
H-FABP is associated with the
dopamine D(2) receptor long
isoform (D2LR) in vitro. Here, we confirm that
H-FABP binds to
dopamine D(2) receptor (D2R) in brain extracts and colocalizes immunohistochemically with D2R in the dorsal striatum. We show that
H-FABP is highly expressed in acetylcholinergic interneurons and terminals of glutamatergic neurons in the dorsal striatum of mouse brain but absent in dopamine neuron terminals and spines in the same region.
H-FABP knock-out (KO) mice showed lower responsiveness to
methamphetamine-induced sensitization and enhanced
haloperidol-induced
catalepsy compared with wild-type mice, indicative of D2R dysfunction. Consistent with the latter, aberrant increased
acetylcholine (ACh) release and depolarization-induced
glutamate (Glu) release were observed in the dorsal striatum of
H-FABP KO mice. Furthermore, phosphorylation of
CaMKII (
Ca(2+)/calmodulin-dependent protein kinase II) and ERK (
extracellular signal-regulated kinase) was significantly increased in the dorsal striatum. We confirmed elevated ERK phosphorylation following
quinpirole-mediated D2R stimulation in
H-FABP-overexpressing SHSY-5Y human
neuroblastoma cells. Together,
H-FABP is highly expressed in ACh interneurons and glutamatergic terminals, thereby regulating
dopamine D2R function in the striatum.