NCX3 deficiency in the prefrontal cortex induces hyperactivity and social deficits via aberrant dopaminergic neurotransmission

Abstract

Na⁺/ Ca²⁺ exchangers (NCXs) are predominantly expressed in neuronal plasma membranes and consist of three mammalian NCX isoforms (NCX1, NCX2, and NCX3). However, the biological function of NCX in the brain still remains unknown. Here, we examined behavioral changes, as well as underlying molecular properties in the NCX3 heterozygous (NCX3^+/-) mice. We found that hyperactivity and social deficits in NCX3^+/- mice, which are ameliorated by the treatment of methylphenidate. In addition, we have identified that NCX3 was localized in the dopaminergic neuron of the ventral tegmental area which was the source of the dopamine innervation of the prefrontal cortex (PFC). In the PFC, NCX3^+/- mice displayed decreased extracellular levels of dopamine triggered by social stimuli and persistent elevation of basal dopamine levels relative to WT mice. In concordance with the increase of extracellular dopamine levels in the PFC, NCX3^+/- mice exhibited the activation of dopamine D1 receptor signaling pathways including PKA and DARPP-32 relative to WT mice in the PFC. Thus, the decreased expression of NCX3 leads to impair dopaminergic neurotransmission in the PFC, which likely accounts for the hyperactivity and social dysfunction in NCX3^+/- mice.