Male reproduction depends on hormonally driven behaviors and numerous genes for testis development and spermatogenesis. Neuroplastin-deficient (Nptn^−/−) male mice cannot sire offspring. By immunohistochemistry, we characterized neuroplastin expression in the testis. Breeding, mating behavior, hormonal regulation, testicular development, and spermatogenesis were analyzed in cell-type specific neuroplastin mutant mice. Leydig, Sertoli, peritubular myoid, and germ cells express Np, but spermatogenesis and sperm number are not affected in Nptn^−/− males. Neuroplastin lack from CNS neurons or restricted to spermatogonia or Sertoli cells permitted reproduction. Normal luteinizing hormone (LH) and follicle-stimulating hormone (FSH) blood levels in Nptn^−/− males support undisturbed hormonal regulation in the brain. However, Nptn^−/− males lack mounting behavior accompanied by low testosterone blood levels. Testosterone rise from juvenile to adult blood levels is absent in Nptn^−/− males. LH-receptor stimulation raising intracellular Ca²⁺ in Leydig cells triggers testosterone production. Reduced Plasma Membrane Ca²⁺ ATPase 1 (PMCA1) in Nptn^−/− Leydig cells suggests that Nptn^−/− Leydig cells produce sufficient testosterone for testis and sperm development, but a lack of PMCA-Np complexes prevents the increase from reaching adult blood levels. Behavioral immaturity with low testosterone blood levels underlies infertility of Nptn^−/− males, revealing that Np is essential for reproduction.

Hearing, the ability to sense sounds, and the processing of auditory information are important for perception of the world. Mice lacking expression of neuroplastin (Np), a type-1 transmembrane glycoprotein, display deafness, multiple cognitive deficiencies, and reduced expression of plasma membrane calcium (Ca²⁺) ATPases (PMCAs) in cochlear hair cells and brain neurons. In this study, we transferred the deafness causing missense mutations pitch (C315S) and audio-1 (I122N) into human Np (hNp) constructs and investigated their effects at the molecular and cellular levels. Computational molecular dynamics show that loss of the disulfide bridge in hNp^pitch causes structural destabilization of immunoglobulin-like domain (Ig) III and that the novel asparagine in hNp^audio-1 results in steric constraints and an additional N-glycosylation site in IgII. Additional N-glycosylation of hNp^audio-1 was confirmed by PNGaseF treatment. In comparison to hNp^WT, transfection of hNp^pitch and hNp^audio-1 into HEK293T cells resulted in normal mRNA levels but reduced the Np protein levels and their cell surface expression due to proteasomal/lysosomal degradation. Furthermore, hNp^pitch and hNp^audio-1 failed to promote exogenous PMCA levels in HEK293T cells. In hippocampal neurons, expression of additional hNp^pitch or hNp^audio-1 was less efficient than hNp^WT to elevate endogenous PMCA levels and to accelerate the restoration of basal Ca²⁺ levels after electrically evoked Ca²⁺ transients. We propose that mutations leading to pathological Np variants, as exemplified here by the deafness causing Np mutants, can affect Np-dependent Ca²⁺ regulatory mechanisms and may potentially cause intellectual and cognitive deficits in humans.

Proper signal transmission is the fundamental process of the brain activity. Changes and adaption of neuroplasticity based on the strength of synaptic transmission are essential for the information propagation in the central nervous system, which contribute to cognition, learning, and memory. Being the major excitatory neurotransmitter in the central nervous system, glutamate acts primarily through binding to the glutamate receptors, the glutamate-gated ion channels localized on post-synaptic membrane. The ionotropic glutamate receptors, pharmacologically grouped into α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors, N-methyl-D-aspartic acid (NMDA) receptors, and kainate receptors, have been shown to play distinct roles in excitatory neurotransmission and synaptic plasticity. Due to their high permeability to Ca2+, the NMDA receptors have very unique function in neurotransmission and particular importance in the induction of long-term synaptic plasticity. Dysfunction of NMDA receptors causes impairment in synaptic plasticity and learning and memory. In recent years, with the development of genome-wide association studies and next-generation sequencing technology, mutations of NMDA receptor subunits have been in a variety of neuropsychiatric disorders, such as cognitive impairment, schizophrenia, autism or epilepsy. In clinical practice, NMDA receptors are known as the targets for the treatment of many neuropsychiatric disorders. In current review, we summarize current knowledge of NMDA receptors with different subunit compositions in the context of expression pattern, channel properties, protein trafficking, and synaptic plasticity as well as their roles in neuropsychiatric disorders.