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<p>Our earlier human studies identified <i>NRSN2</i> (Neurensin-2), a neuronal-specific vesicular protein, as a candidate gene contributing to 20p13 microdeletion syndrome, yet the functional consequences of <i>NRSN2</i> deficiency in the nervous system remain poorly understood. To explore the role of <i>Nrsn2</i> in neurodevelopment and cognitive function, we utilized previously generated homozygous <i>Nrsn2</i> knockout mice (<i>Nrsn2</i><sup>-/-</sup>) and performed a series of behavioral, morphological, and electrophysiological analyses. Behaviorally, <i>Nrsn2</i><sup>-/-</sup> mice exhibited mild locomotor impairment, as assessed by gait analysis at 4 and 8 weeks of age, as well as significant deficits in spatial learning and memory (Morris water maze) and fear memory (passive avoidance test) at 8 weeks. Morphometric analysis suggested no overt alterations in dendritic complexity or spine density in hippocampal CA1 pyramidal neurons or cerebellar Purkinje cells without developmental malformation. Electrophysiological recordings and immunoblotting analyses may reflect region-specific synaptic alterations. In the hippocampus, expression levels of the NMDA receptor subunits GluN1 and GluN2A were reduced at 4 weeks of age. Consistently, CA1 pyramidal neurons displayed decreased sEPSC frequency with unchanged amplitude under the conditions examined. In addition, an imbalance in hippocampal excitatory/inhibitory transmission was observed, as reflected by altered sEPSC frequency in the absence of changes in sIPSC frequency. In cerebellar Purkinje cells, GluA1-containing AMPA receptors were selectively downregulated, accompanied by reduced frequency and amplitude of sEPSCs and a selective decrease in sIPSC frequency, indicating both excitatory and inhibitory synaptic dysfunction in this region. Collectively, these findings indicate that <i>Nrsn2</i> deficiency is accompanied by altered excitatory synaptic transmission and reduced long-term potentiation (LTP) at 8 weeks of age, despite preserved dendritic architecture as assessed by Golgi staining. These synaptic and plasticity deficits occur alongside the observed cognitive and motor impairments in <i>Nrsn2</i><sup>⁻/⁻</sup> mice. This study provides a descriptive phenotypic characterization of <i>Nrsn2</i> deficiency and offers initial insights into the neurobiological role of <i>NRSN2</i> and its contribution to neurodevelopment, learning, and memory.</p>

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Impact of NRSN2 deficiency on memory: Altered excitatory synaptic plasticity associated with reduced expression of NMDA receptor subunits and impaired LTP in the hippocampus

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年6月20日

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  • Jialu Wei,
  • Yongkang Wu,
  • Yuan Yi,
  • Yixia Gan,
  • Haibo Li,
  • Lingbo Wang,
  • Yiping Shen,
  • Yi Dong,
  • Yu An

摘要

Our earlier human studies identified NRSN2 (Neurensin-2), a neuronal-specific vesicular protein, as a candidate gene contributing to 20p13 microdeletion syndrome, yet the functional consequences of NRSN2 deficiency in the nervous system remain poorly understood. To explore the role of Nrsn2 in neurodevelopment and cognitive function, we utilized previously generated homozygous Nrsn2 knockout mice (Nrsn2-/-) and performed a series of behavioral, morphological, and electrophysiological analyses. Behaviorally, Nrsn2-/- mice exhibited mild locomotor impairment, as assessed by gait analysis at 4 and 8 weeks of age, as well as significant deficits in spatial learning and memory (Morris water maze) and fear memory (passive avoidance test) at 8 weeks. Morphometric analysis suggested no overt alterations in dendritic complexity or spine density in hippocampal CA1 pyramidal neurons or cerebellar Purkinje cells without developmental malformation. Electrophysiological recordings and immunoblotting analyses may reflect region-specific synaptic alterations. In the hippocampus, expression levels of the NMDA receptor subunits GluN1 and GluN2A were reduced at 4 weeks of age. Consistently, CA1 pyramidal neurons displayed decreased sEPSC frequency with unchanged amplitude under the conditions examined. In addition, an imbalance in hippocampal excitatory/inhibitory transmission was observed, as reflected by altered sEPSC frequency in the absence of changes in sIPSC frequency. In cerebellar Purkinje cells, GluA1-containing AMPA receptors were selectively downregulated, accompanied by reduced frequency and amplitude of sEPSCs and a selective decrease in sIPSC frequency, indicating both excitatory and inhibitory synaptic dysfunction in this region. Collectively, these findings indicate that Nrsn2 deficiency is accompanied by altered excitatory synaptic transmission and reduced long-term potentiation (LTP) at 8 weeks of age, despite preserved dendritic architecture as assessed by Golgi staining. These synaptic and plasticity deficits occur alongside the observed cognitive and motor impairments in Nrsn2⁻/⁻ mice. This study provides a descriptive phenotypic characterization of Nrsn2 deficiency and offers initial insights into the neurobiological role of NRSN2 and its contribution to neurodevelopment, learning, and memory.