Systemic Copper Disorders Influence the Olfactory Function in Adult Rats: Roles of Altered Adult Neurogenesis and Neurochemical Imbalance

Abstract

Disrupted systemic copper (Cu) homeostasis underlies neurodegenerative diseases with early symptoms including olfactory dysfunction. This study investigated the impact of Cu dyshomeostasis on olfactory function, adult neurogenesis, and neurochemical balance. Models of Cu deficiency (CuD) and Cu overload (CuO) were established by feeding adult rats with Cu-restricted diets plus ip. injection of a Cu chelator (ammonium tetrathiomolybdate) and excess Cu, respectively. CuD reduced Cu levels in the olfactory bulb (OB), subventricular zone (SVZ), rostral migratory stream (RMS), and striatum, while CuO increased Cu levels in these areas. The buried pellet test revealed both CuD and CuO prolonged the latency to uncover food. CuD increased neural proliferation and stem cells in the SVZ and newly differentiated neurons in the OB, whereas CuO caused opposite alterations, suggesting a “switch”-type function of Cu in regulating adult neurogenesis. CuO increased GABA in the OB, while both CuD and CuO reduced DOPAC, HVA, 5-HT and the DA turnover rate in olfactory-associated brain regions. Altered mRNA expression of Cu transport and storage proteins in tested brain areas were observed under both conditions. Together, results support an association between systemic Cu dyshomeostasis and olfactory dysfunction. Specifically, altered adult neurogenesis along the SVZ-RMS-OB pathway and neurochemical imbalance could be the factors that may contribute to olfactory dysfunction.

Copper Modulates Adult Neurogenesis in Brain Subventricular Zone

“…The choroid plexus plays a critical role in regulating Cu homeostasis in the CSF [ 49 , 50 , 51 ]. The current finding on a significant increase of CTR1 in the choroid plexus after D-Pen chelation of Cu is in a good agreement with the literature reports by systematic Cu deficiency induced by restricting dietary Cu [ 24 , 52 ]. Given the anatomical closeness of the choroid plexus to the SVZ in brain ventricle and the fluid communication between the two via the CSF, it is reasonable to postulate that changes in Cu-regulatory functions in the choroid plexus may modulate adult neurogenesis in nearby SVZ.…”

“…Data in this study also showed an upregulated MT3 expression in the SVZ following ICV D-Pen infusion in a dose-dependent manner, which is consistent with the result from the systemic Cu-deficiency model by this lab [ 24 ]. This may indicate a compensatory mechanism by which the Cu-depleted cells demanded more Cu for intracellular storage.…”

“…Our recent work has established that systematic Cu disorders in adult rats can alter SVZ neurogenesis, leading to neurochemical imbalance in the SVZ-RMS-OB axis [ 24 ]. The Cu concentrations along the SVZ-RMS-OB axis in that study change significantly in both Cu-deficient and Cu-overload animals.…”

“…How then does Cu regulate the adult neurogenesis in the SVZ? Extensive reports in the literature have linked Cu to neuronal differentiation, synaptic signal transduction, and neurodegeneration [ 24 , 53 , 54 , 55 , 56 ]. However, a role of Cu in neurogenesis, no matter in early postnatal phase or in adult brain, remains elusive; even less is known about the molecular regulatory mechanism taking place in the SVZ-RMS-OB axis.…”

“…Third, directly delivering Cu ions to the cerebrospinal fluid (CSF) by intracerebroventricular (ICV) injections apparently suppressed the NSPC proliferation in the SVZ [ 16 ]. Finally, a recent report by this lab modeling systemic Cu overload in rats further revealed that the SVZ adult neurogenesis was significantly downregulated in brains of Cu-overladed animals [ 24 ]. These observations prompted us to propose a Cu-dependent regulatory mechanism in the SVZ, where a naturally high Cu level in the SVZ may suppress the adult neurogenesis in a state of “switching-off”, whereas a reduced SVZ Cu may “switch on” the neurogenesis, thus increasing the proliferation, migration, and differentiation of NSPCs along the SVZ-RMS-OB axis.…”