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，胎儿酒精谱系障碍（FASD）中出现的许多神经功能缺陷是神经可塑性差的基础。神经元的可塑性涉及连接的建立和断开，而连接又与神经元反应的增强和抑制有关。这些过程在初级视觉皮层的眼优势可塑性中是明显的。这种模式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学皮层变化。因此，在正常动物中，几天的MD会导致被剥夺（闭）眼驱动的神经元反应下降，而被体验（开）眼驱动的神经元反应增强。利用雪貂模型，我们在过去证明了早期酒精暴露会导致眼优势可塑性（ODP）的永久性损伤。随后，不同的研究小组利用ODP研究脆性X、新生儿缺氧缺血和Angelmann综合征模型中的神经元可塑性。我们对雪貂的研究结合了固有信号的光学成像和单单元记录（体内细胞外电生理）。在这里，我们将结合体内和体外电生理学技术来梳理早期酒精暴露（EAE）对神经元可塑性的机制。具体来说，我们将验证以下假设：A) EAE可能通过影响谷氨酸能神经传递，破坏皮层第四层反应的增强而不是抑制。B) EAE可能通过对谷氨酸能和内源性大麻素神经传递的联合作用，破坏皮层II/III层反应的增强和抑制。最后C)长春西汀和咖啡因对1型磷酸二酯酶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。测试咖啡因具有特殊的意义，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.