Early impairment of cortical circuit plasticity and connectivity in the 5XFAD Alzheimer's disease mouse model.
Early impairment of cortical circuit plasticity and connectivity in the 5XFAD Alzheimer's disease mouse model.
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DOI：
10.1038/s41398-022-02132-4
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发表时间：
2022-09-08
影响因子：
6.8
通讯作者：
Qiu, Shenfeng
中科院分区：
文献类型：
--
作者：
Chen, Chang;Ma, Xiaokuang;Wei, Jing;Shakir, Neha;Zhang, Jessica K.;Zhang, Le;Nehme, Antoine;Cui, Yuehua;Ferguson, Deveroux;Bai, Feng;Qiu, Shenfeng
神经退行性疾病（如阿尔茨海默病（AD））的遗传风险因素在整个生命周期中都有表达。这些风险因素如何影响早期大脑发育和功能在很大程度上仍不清楚。对AD具有高建设性有效性的动物模型（如5xFAD小鼠模型）进行分析，可能会对影响成人脑功能和年龄依赖性变性的潜在早期神经发育影响提供见解。5XFAD小鼠模型过表达人淀粉样前体蛋白（APP）和早老素1（PS1），携带5个家族性AD突变。目前还不清楚这些突变蛋白的表达如何影响早期发育的大脑回路。我们发现，前额叶皮层（PFC）层5（L5）神经元在5XFAD小鼠表现出转基因APP超载在早期断奶后的年龄。6-8周龄L5 PFC回路突触可塑性（LTP）受损，与细胞内APP增加有关; 4 - 5周龄L5初级视皮层（V1）锥体神经元在可塑性关键期（4-5周龄）APP超载。在V1脑切片中的全细胞膜片钳记录揭示了在5XFAD小鼠中L5神经元的固有兴奋性降低，沿着自发的微小兴奋性和抑制性输入降低。使用激光扫描光刺激（LSPS）结合谷氨酸释放的功能电路映射发现，在V1中，L5神经元上的兴奋性突触连接减少，抑制性连接减少更明显，表明VC关键期的兴奋和抑制改变。最后，在V1中的体内单单位记录证实，在5XFAD小鼠中，单眼视觉剥夺诱导的眼优势可塑性在关键期受损。我们的研究揭示了多个皮层区域的可塑性缺陷，并表明由于突变APP/PS1过表达而改变了早期皮层回路的发育轨迹。
Genetic risk factors for neurodegenerative disorders, such as Alzheimer’s disease (AD), are expressed throughout the life span. How these risk factors affect early brain development and function remain largely unclear. Analysis of animal models with high constructive validity for AD, such as the 5xFAD mouse model, may provide insights on potential early neurodevelopmental effects that impinge on adult brain function and age-dependent degeneration. The 5XFAD mouse model over-expresses human amyloid precursor protein (APP) and presenilin 1 (PS1) harboring five familial AD mutations. It is unclear how the expression of these mutant proteins affects early developing brain circuits. We found that the prefrontal cortex (PFC) layer 5 (L5) neurons in 5XFAD mice exhibit transgenic APP overloading at an early post-weaning age. Impaired synaptic plasticity (long-term potentiation, LTP) was seen at 6–8 weeks age in L5 PFC circuit, which was correlated with increased intracellular APP. APP overloading was also seen in L5 pyramidal neurons in the primary visual cortex (V1) during the critical period of plasticity (4–5 weeks age). Whole-cell patch clamp recording in V1 brain slices revealed reduced intrinsic excitability of L5 neurons in 5XFAD mice, along with decreased spontaneous miniature excitatory and inhibitory inputs. Functional circuit mapping using laser scanning photostimulation (LSPS) combined with glutamate uncaging uncovered reduced excitatory synaptic connectivity onto L5 neurons in V1, and a more pronounced reduction in inhibitory connectivity, indicative of altered excitation and inhibition during VC critical period. Lastly, in vivo single-unit recording in V1 confirmed that monocular visual deprivation-induced ocular dominance plasticity during critical period was impaired in 5XFAD mice. Our study reveals plasticity deficits across multiple cortical regions and indicates altered early cortical circuit developmental trajectory as a result of mutant APP/PS1 over-expression.
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影响因子：
3.6
作者：
Hwang KD;Bak MS;Kim SJ;Rhee S;Lee YS
通讯作者：
Lee YS
影响因子：
4.6
作者：
Koppensteiner P;Trinchese F;Fà M;Puzzo D;Gulisano W;Yan S;Poussin A;Liu S;Orozco I;Dale E;Teich AF;Palmeri A;Ninan I;Boehm S;Arancio O
通讯作者：
Arancio O
影响因子：
15.1
作者：
Benitez DP;Jiang S;Wood J;Wang R;Hall CM;Peerboom C;Wong N;Stringer KM;Vitanova KS;Smith VC;Joshi D;Saito T;Saido TC;Hardy J;Hanrieder J;De Strooper B;Salih DA;Tripathi T;Edwards FA;Cummings DM
通讯作者：
Cummings DM
影响因子：
4.2
作者：
Jawhar, Sadim;Trawicka, Anna;Wirths, Oliver
通讯作者：
Wirths, Oliver
影响因子：
25
作者：
Herzig, MC;Winkler, DT;Jucker, M
通讯作者：
Jucker, M