Improving Neuronal Plasticity in a Mouse Model of FASD

描述(由申请人提供)：越来越多的证据表明，神经元可塑性差是胎儿酒精谱系障碍(FASD)许多神经缺陷的基础。神经元可塑性涉及连接的建立和断开，而连接的建立和断开又与神经元反应的增强和抑制有关。这些过程在初级视皮层中眼优势的可塑性中表现得很明显。这一范例是基于在发育的关键时期通过眼睑缝合进行单眼剥夺(MD)后发生的功能和形态上的皮质变化。因此，在正常动物中，几天的MD会导致剥夺(闭合)眼睛驱动的神经元反应的抑制，以及经验丰富(睁开的)眼睛驱动的神经元反应的增强。使用雪貂模型，我们在过去证明了早期酒精暴露会导致眼睛优势可塑性(ODP)的永久性损害。随后，在脆性X、新生儿缺氧缺血和Angelmann综合征模型中，不同的研究小组使用了ODP法来研究神经元的可塑性。我们在雪貂身上的研究使用了内在信号的光学成像和单一单元记录(活体细胞外电生理学)相结合的方法。在这里，我们将结合体内和体外的电生理学技术，梳理出早期酒精暴露(EAE)对神经元可塑性的机制。具体地说，我们将检验以下假设：a)EAE可能通过影响谷氨酸能神经传递来干扰皮质IV层反应的增强而不是抑制。B)EAE干扰皮层II/III层反应的增强和抑制，可能是通过对谷氨酸能神经传递和内源性大麻素神经传递的联合作用。最后，长春西汀和咖啡因对磷酸二酯酶1型的抑制将恢复酒精暴露小鼠神经元可塑性的增强和抑制成分。测试咖啡因将具有特别的相关性，因为这种药物通常被用作早产儿的治疗干预，这可能有助于将其转化为FASD受试者。

DESCRIPTION (provided by applicant): There is growing evidence that poor neuronal plasticity underlies many of the neurological deficits seen in Fetal Alcohol Spectrum Disorders (FASD). Neuronal plasticity involves making and breaking connections, which in turn are related to potentiation and depression of neuronal responses. These processes are evident in the plasticity of ocular dominance in primary visual cortex. This paradigm is based on functional and morphological cortical changes that occur after a monocular deprivation (MD) by eyelid suture is performed during a critical period of development. Accordingly, in normal animals few days of MD lead to a depression of responses of neurons driven by the deprived (closed) eye, and a potentiation of responses in neurons driven by the experienced (open) eye. Using a ferret model, we demonstrated in the past that early alcohol exposure leads to a permanent impairment in ocular dominance plasticity (ODP). Subsequently, ODP has been used by different groups to study neuronal plasticity in models of Fragile X, Neonatal-Hypoxia ischemia and Angelmann Syndrome. Our studies in ferrets used a combination of optical imaging of intrinsic signals and single unit recordings (in vivo extracellular electrophysiology). Here we wil use a combination of in vivo and in vitro electrophysiology techniques to tease out the mechanisms of early alcohol exposure (EAE) on neuronal plasticity. Specifically we will test the following hypothesis: A) EAE disrupts potentiation BUT NOT depression of responses in cortical layer IV, possibly by affecting glutamatergic neurotransmission. B) EAE disrupts BOTH potentiation and depression of responses in cortical layer II/III possibly by a combined effect on glutamatergic and endocannabinoid neurotransmission. And finally C) That phosphodiesterase type 1 inhibition by vinpocetine and caffeine will restore both potentiation and depression components of neuronal plasticity in alcohol exposed mice. Testing caffeine would be of particular relevance because this drug is routinely used as a therapeutic intervention in premature babies, which could facilitate its translation to FASD subjects.