Medical Psychology Unit, Department of Psychiatry and Forensic Medicine, Institute of Neurosciences, School of Medicine, Universidad Autónoma de Barcelona, 08193 Bellaterra, Barcelona, Spain; Department of Physiology and Biophysics, Virginia Commonwealth University School of Medicine, Richmond, VA, USA.
Research Laboratory for Stereology and Neuroscience, Bispebjerg Copenhagen University Hospital, 2400 Copenhagen, Denmark.
Eur Neuropsychopharmacol. 2021 Mar;44:79-91. doi: 10.1016/j.euroneuro.2021.01.006. Epub 2021 Jan 21.
The cellular mechanisms altered during brain wiring leading to cognitive disturbances in neurodevelopmental disorders remain unknown. We have previously reported altered cortical expression of neurodevelopmentally regulated synaptic markers in a genetic animal model of schizophrenia-relevant behavioral features, the Roman-High Avoidance rat strain (RHA-I). To further explore this phenotype, we looked at dendritic spines in cortical pyramidal neurons, as changes in spine density and morphology are one of the main processes taking place during adolescence. An HSV-viral vector carrying green fluorescent protein (GFP) was injected into the frontal cortex (FC) of a group of 11 RHA-I and 12 Roman-Low Avoidance (RLA-I) male rats. GFP labeled dendrites from pyramidal cells were 3D reconstructed and number and types of spines quantified. We observed an increased spine density in the RHA-I, corresponding to a larger fraction of immature thin spines, with no differences in stubby and mushroom spines. Glia cells, parvalbumin (PV) and somatostatin (SST) interneurons and surrounding perineuronal net (PNN) density are known to participate in FC and pyramidal neuron dendritic spine maturation. We determined by stereological-based quantification a significantly higher number of GFAP-positive astrocytes in the FC of the RHA-I strain, with no difference in microglia (Iba1-positive cells). The number of inhibitory PV, SST interneurons or PNN density, on the contrary, was unchanged. Results support our belief that the RHA-I strain presents a more immature FC, with some structural features like those observed during adolescence, adding construct validity to this strain as a genetic behavioral model of neurodevelopmental disorders.
在导致神经发育障碍认知障碍的大脑连接过程中改变的细胞机制尚不清楚。我们之前曾报道过，在与精神分裂症相关行为特征相关的遗传动物模型，即罗马高回避大鼠（RHA-I）中，神经发育调节性突触标记物的皮质表达发生改变。为了进一步探索这种表型，我们观察了皮质锥体神经元中的树突棘，因为在青春期期间，棘密度和形态的变化是主要发生的过程之一。携带绿色荧光蛋白（GFP）的 HSV 病毒载体被注射到一组 11 只 RHA-I 和 12 只罗马低回避（RLA-I）雄性大鼠的额皮质（FC）中。GFP 标记了来自锥体细胞的树突进行了 3D 重建，并定量了棘的数量和类型。我们观察到 RHA-I 中的棘密度增加，对应于更大比例的不成熟的细棘，而短粗棘和蘑菇棘没有差异。胶质细胞、parvalbumin（PV）和 somatostatin（SST）中间神经元以及周围的 perineuronal net（PNN）密度已知参与 FC 和锥体神经元树突棘成熟。我们通过基于立体学的定量确定 RHA-I 品系 FC 中的 GFAP 阳性星形胶质细胞数量显著增加，而小胶质细胞（Iba1 阳性细胞）没有差异。相反，抑制性 PV、SST 中间神经元或 PNN 密度的数量没有变化。结果支持我们的信念，即 RHA-I 品系表现出更不成熟的 FC，具有类似于青春期观察到的一些结构特征，为该品系作为神经发育障碍的遗传行为模型增加了结构有效性。
