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 Nptnlox/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 Nptnlox/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.
Highlights
Learning and memory depend on balanced excitation and inhibition in neuronal networks interconnected via synapses[1,2,3,4,5]
As Np expression has not been sufficiently characterized in human brain, we investigated the expression and molecular characteristics of human Np further
Preservation of human Np (hNp) immunoreactivity, specificity of pan-Np55/65 and anti-Np65 antibodies and reliability of our immunohistochemistry procedures were demonstrated with hippocampal slices from 4 or 8 days post-mortem wild-type and Nptn−/− mice prepared under similar conditions as the human samples (Supplementary Fig. S1)
Summary
Learning and memory depend on balanced excitation and inhibition in neuronal networks interconnected via synapses[1,2,3,4,5]. In contrast Nptn−/− mice, completely devoid of Np expression, are not deaf but display loss of fear-conditioned associative learning, altered sensorimotor capabilities, complex swimming and diving behaviors www.nature.com/scientificreports/. Neuron-specific Nptn gene inactivation in adult Nptnlox/loxPrpCreERT mice triggered hippocampal and cortical alterations and induced retrograde amnesia of associative memories assigning a unique role to Np in cognitive functions[10]. Important information necessary to relate behavioral deficiencies in Np mouse models to specific human brain functions is missing. In Nptn−/− and Nptnlox/loxPrpCreERT mice, PMCA expression levels are severely reduced[10]. These high-affinity Ca2+-pumps, but no other mechanisms, are capable to fully restore basal [iCa2+] in all eukaryotic cells[21, 22]. Despite alterations in the expression of PMCA paralogs and their association to impaired [iCa2+] handling in autism[29, 30], schizophrenia[31], Alzheimer’s disease[32, 33], Niemann-Pick disease[34], deafness[35], and spinocerebellar ataxia[36, 37], mechanisms leading to altered levels of PMCA paralogs remain largely unsolved
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