Gener Thomas, Hidalgo-Nieves Sara, López-Cabezón Cristina, Puig Maria Victoria
Department of Neuroscience and Experimental Therapeutics, Institute of Biomedical Research of Barcelona, CSIC, 08036 Barcelona, Spain.
Catalan Institute of Nanoscience and Nanotechnology (ICN2), CSIC and BIST, Campus UAB, 08193 Bellaterra, Spain.
Int J Mol Sci. 2025 Apr 12;26(8):3659. doi: 10.3390/ijms26083659.
We investigated the cellular and neurophysiological mechanisms underlying the pro-cognitive effects of 5-HT4R activation in hippocampal-prefrontal pathways. Our findings show that, in addition to pyramidal neurons, 30-60% of parvalbumin+ interneurons in the CA1, CA3, and dentate gyrus (DG) of the hippocampus and the anterior cingulate (ACC), prelimbic (PL), and infralimbic (IL) regions of the prefrontal cortex co-express 5-HT4Rs. Additionally, 15% of somatostatin+ interneurons in CA1 and CA3 express 5-HT4Rs. Partial 5-HT4R agonist RS-67333 (1 mg/kg, i.p.) exerted anxiolytic effects and ameliorated short-term (3-min) and long-term (24-h) memory deficits in a mouse model of schizophrenia-like cognitive impairment induced by sub-chronic phencyclidine (sPCP) but did not enhance memory in healthy mice. At the neurophysiological level, RS-67333 normalized sPCP-induced disruptions in hippocampal-prefrontal neural dynamics while having no effect in healthy animals. Specifically, sPCP increased delta oscillations in CA1 and PL, leading to aberrant delta-high-frequency coupling in CA1 and delta-high-gamma coupling in PL. RS-67333 administration attenuated this abnormal delta synchronization without altering phase coherence or signal directionality within the circuit. Collectively, these results highlight the therapeutic potential of 5-HT4R activation in pyramidal, parvalbumin+, and somatostatin+ neurons of hippocampal-prefrontal pathways for mitigation of cognitive and negative symptoms associated with schizophrenia.
我们研究了海马-前额叶通路中5-羟色胺4受体（5-HT4R）激活产生促认知作用的细胞和神经生理机制。我们的研究结果表明，除了锥体神经元外，海马体的CA1、CA3和齿状回（DG）以及前额叶皮质的前扣带回（ACC）、边缘前区（PL）和边缘下区（IL）中，30%-60%的小白蛋白阳性中间神经元共表达5-HT4R。此外，CA1和CA3中15%的生长抑素阳性中间神经元表达5-HT4R。部分5-HT4R激动剂RS-67333（1毫克/千克，腹腔注射）在由亚慢性苯环利定（sPCP）诱导的精神分裂症样认知障碍小鼠模型中发挥抗焦虑作用，并改善了短期（3分钟）和长期（24小时）记忆缺陷，但对健康小鼠的记忆没有增强作用。在神经生理水平上，RS-67333使sPCP诱导的海马-前额叶神经动力学破坏恢复正常，而对健康动物没有影响。具体而言，sPCP增加了CA1和PL中的δ振荡，导致CA1中异常的δ-高频耦合以及PL中δ-高γ耦合。给予RS-67333可减弱这种异常的δ同步，而不改变回路内的相位相干性或信号方向性。总的来说，这些结果突出了激活海马-前额叶通路中锥体神经元、小白蛋白阳性神经元和生长抑素阳性神经元中的5-HT4R在减轻与精神分裂症相关的认知和阴性症状方面的治疗潜力。
