Neuroplastin deletion in glutamatergic neurons impairs selective brain functions and calcium regulation: implication for cognitive deterioration

Abstract

The cell adhesion molecule neuroplastin (Np) is a novel candidate to influence human intelligence. Np-deficient mice display complex cognitive deficits and reduced levels of Plasma Membrane Ca2+ ATPases (PMCAs), an essential regulator of the intracellular Ca2+ concentration ([iCa2+]) and neuronal activity. We show abundant expression and conserved cellular and molecular features of Np in glutamatergic neurons in human hippocampal-cortical pathways as characterized for the rodent brain. In Nptn lox/loxEmx1Cre mice, glutamatergic neuron-selective Np ablation resulted in behavioral deficits indicating hippocampal, striatal, and sensorimotor dysfunction paralleled by highly altered activities in hippocampal CA1 area, sensorimotor cortex layers I-III/IV, and the striatal sensorimotor domain detected by single-photon emission computed tomography. Altered hippocampal and cortical activities correlated with reduction of distinct PMCA paralogs in Nptn lox/loxEmx1Cre mice and increased [iCa2+] in cultured mutant neurons. Human and rodent Np enhanced the post-transcriptional expression of and co-localized with PMCA paralogs in the plasma membrane of transfected cells. Our results indicate Np as essential for PMCA expression in glutamatergic neurons allowing proper [iCa2+] regulation and normal circuit activity. Neuron-type-specific Np ablation empowers the investigation of circuit-coded learning and memory and identification of causal mechanisms leading to cognitive deterioration.

Hippocampal expression of cell‐adhesion glycoprotein neuroplastin is altered in Alzheimer's disease

“…Human Np65 was found to specifically localize on the neuronal membranes and in neuropil, while the overall Np immunoreactivity is distributed throughout distinct neuron‐containing hippocampal sublayers in both AD and control hippocampi (Figure ). The highest Np signal in normal human hippocampus is present in the CA1 area and dentate gyrus, > CA2/3, > hilus, > subiculum, and is specifically expressed in sublayers containing pyramidal or granule cells, as reported previously …”

“…Studies in literature have indicated multiple different (patho)physiological functions of cell‐adhesion molecule (CAM) neuroplastin in the human brain such as: the association of neuroplastin gene polymorphisms with cognitive abilities and cortical thickness in adolescents; single nucleotide polymorphisms that are associated with a higher risk of developing schizophrenia . Also, we recently reported that immunohistochemical localization of neuroplastin in the adult human hippocampus specifically delineates hippocampal circuitry and its principal excitatory pathways, and that there is a link between Np expression and calcium regulation in murine cortical hippocampal glutamatergic neurons . Two isoforms of neuroplastin, Np55 and brain‐specific Np65, have been described .…”

“…Neuroplastin functions in several vital processes in the mammalian central nervous system including neurite outgrowth, regulation of synaptic plasticity, long‐term potentiation, maintaining balance between the excitatory and inhibitory pathways and the formation of associative memory . Data from mice and rats have allowed us to determine that neuroplastin has a high preference for the hippocampus and cerebellum, but only two studies have systematically analysed Np expression in human brains . As with other CAMs, it is presumed that Np is involved in the molecular events which underlay the structural and functional processes of brain development, ageing, and neurodegeneration .…”

Neuroplastin 65 modulates anxiety‐ and depression‐like behavior likely through adult hippocampal neurogenesis and central 5‐HT activity

“…Additionally, Np65 KO mice showed enhanced social interaction and some aspects of reduced depressive behavior as compared with the WT mice. Finally, Np65 KO mice exhibited [25] reported that Nptn ablation in glutamatergic neurons (Nptn lox/lox Emx1Cre mice) did not disturb formation of spatial memory but showed the discontinuity of swimming action with repetitive pause-swimming cycles and the swimming strategy in reversal probe test. They also reported reduced PMCAs in Nptn À/À mice, inducible Nptn KO mice and Nptn lox/lox Emx1Cre mice, which may be correlated with the altered behaviors [24,25].…”

“… reported that Nptn ablation in glutamatergic neurons (Nptn lox/lox Emx1Cre mice) did not disturb formation of spatial memory but showed the discontinuity of swimming action with repetitive pause–swimming cycles and the swimming strategy in reversal probe test. They also reported reduced PMCAs in Nptn −/− mice, inducible Nptn KO mice and Nptn lox/lox Emx1Cre mice, which may be correlated with the altered behaviors . The behavioral differences between Np65 KO and Nptn KO mice may be due to these two mouse models having different genetic deletions.…”