The learning and memory network is highly complex and remains unclear. The hippocampus is the location of learning and memory function. Impairment of synaptic morphology and synaptic plasticity (i.e., long-term potentiation) appears to cause learning and memory deficits. Several studies have indicated the role of NRXN1 in regulating the synaptic function, but little is known on its role in learning and memory dysfunction associated with attention deficit and hyperactivity disorder (ADHD). Our results showed that overexpression and interference of NRXN1 in vivo, respectively, affected learning and memory, as was assessed by Morris water maze tests, in spontaneously hypertensive rats (SHRs) and Sprague Dawley (SD) rats. We found that SD rats performed better after methylphenidate (MPH) treatment in salvage trials. Accordingly, the change of NRXN1 led to altered synapse-related gene (PSD95, SYN1, GAP43, NLGN1) expression, further providing evidence of its role in the maintenance of synaptic plasticity. We also verified that the expression of synapse-related genes synchronously changed with NRXN1expression in the behavioral assessment. The expression of NRXN1 was confirmed to affect the expression of synapse-related genes after its interference and overexpression in the primary hippocampal neurons in vitro. These results confirmed our hypothesis that NRXN1 might nucleate an overall trans-synaptic signaling network that controls synaptic plasticity and is responsible for impairments in learning and memory in ADHD. These findings suggest a possible protective role of NRXN1 in learning and memory in ADHD. Further RNA-seq sequencing revealed significant differences in the expression of 5-hydroxytryptamine receptor (5-HT₆R), which was further verified at the cellular level, and the mechanism of NRXN1 affecting synaptic plasticity was preliminarily discussed.

学习和记忆网络高度复杂且仍不清楚。海马体是学习和记忆功能的所在地。突触形态和突触可塑性（即长期增强）的损害似乎会导致学习和记忆缺陷。几项研究表明NRXN1在调节突触功能中的作用，但对其在与注意力缺陷和多动障碍 (ADHD) 相关的学习和记忆功能障碍中的作用知之甚少。我们的结果表明NRXN1 的过表达和干扰在自发性高血压大鼠 (SHR) 和 Sprague Dawley (SD) 大鼠中， 体内 分别影响学习和记忆，正如通过莫里斯水迷宫试验评估的那样。我们发现在挽救试验中，哌甲酯 (MPH) 治疗后 SD 大鼠表现更好。因此，NRXN1的变化导致突触相关基因（PSD95、SYN1、GAP43、NLGN1）表达的改变，进一步证明了其在维持突触可塑性中的作用。我们还验证了在行为评估中突触相关基因的表达与NRXN1表达同步变化。NRXN1的表达被证实在体外原代海马神经元中干扰和过度表达后影响突触相关基因的表达。这些结果证实了我们的假设，即NRXN1可能使整个跨突触信号网络成核，该网络控制突触可塑性并导致 ADHD 学习和记忆障碍。这些发现表明NRXN1在 ADHD 的学习和记忆中可能具有保护作用。进一步的RNA-seq测序揭示了5-羟色胺受体（5-HT ₆ R）表达的显着差异，这在细胞水平得到了进一步验证，并初步探讨了NRXN1影响突触可塑性的机制。