Ruiz-Mejias Marcel, Martinez de Lagran Maria, Mattia Maurizio, Castano-Prat Patricia, Perez-Mendez Lorena, Ciria-Suarez Laura, Gener Thomas, Sancristobal Belen, García-Ojalvo Jordi, Gruart Agnès, Delgado-García José M, Sanchez-Vives Maria V, Dierssen Mara
Systems Neuroscience, August Pi i Sunyer Biomedical research Institute (IDIBAPS), 08036 Barcelona, Spain.
Centre for Genomic Regulation (CRG), Barcelona Institute of Science and Technology, 08003 Barcelona, Spain, Pompeu Fabra University (UPF), 08003 Barcelona, Spain, Centre for Biomedical Research on Rare Diseases (CIBERER) 08003 Barcelona, Spain.
J Neurosci. 2016 Mar 30;36(13):3648-59. doi: 10.1523/JNEUROSCI.2517-15.2016.
The dual-specificity tyrosine phosphorylation-regulated kinase DYRK1A is a serine/threonine kinase involved in neuronal differentiation and synaptic plasticity and a major candidate of Down syndrome brain alterations and cognitive deficits. DYRK1A is strongly expressed in the cerebral cortex, and its overexpression leads to defective cortical pyramidal cell morphology, synaptic plasticity deficits, and altered excitation/inhibition balance. These previous observations, however, do not allow predicting how the behavior of the prefrontal cortex (PFC) network and the resulting properties of its emergent activity are affected. Here, we integrate functional, anatomical, and computational data describing the prefrontal network alterations in transgenic mice overexpressingDyrk1A(TgDyrk1A). Usingin vivoextracellular recordings, we show decreased firing rate and gamma frequency power in the prefrontal network of anesthetized and awakeTgDyrk1Amice. Immunohistochemical analysis identified a selective reduction of vesicular GABA transporter punctae on parvalbumin positive neurons, without changes in the number of cortical GABAergic neurons in the PFC ofTgDyrk1Amice, which suggests that selective disinhibition of parvalbumin interneurons would result in an overinhibited functional network. Using a conductance-based computational model, we quantitatively demonstrate that this alteration could explain the observed functional deficits including decreased gamma power and firing rate. Our results suggest that dysfunction of cortical fast-spiking interneurons might be central to the pathophysiology of Down syndrome.
DYRK1Ais a major candidate gene in Down syndrome. Its overexpression results into altered cognitive abilities, explained by defective cortical microarchitecture and excitation/inhibition imbalance. An open question is how these deficits impact the functionality of the prefrontal cortex network. Combining functional, anatomical, and computational approaches, we identified decreased neuronal firing rate and deficits in gamma frequency in the prefrontal cortices of transgenic mice overexpressingDyrk1A We also identified a reduction of vesicular GABA transporter punctae specifically on parvalbumin positive interneurons. Using a conductance-based computational model, we demonstrate that this decreased inhibition on interneurons recapitulates the observed functional deficits, including decreased gamma power and firing rate. Our results suggest that dysfunction of cortical fast-spiking interneurons might be central to the pathophysiology of Down syndrome.
双特异性酪氨酸磷酸化调节激酶DYRK1A是一种丝氨酸/苏氨酸激酶，参与神经元分化和突触可塑性，是唐氏综合征大脑改变和认知缺陷的主要候选因素。DYRK1A在大脑皮层中强烈表达，其过表达会导致皮质锥体细胞形态缺陷、突触可塑性缺陷以及兴奋/抑制平衡改变。然而，这些先前的观察结果无法预测前额叶皮层（PFC）网络的行为及其涌现活动的最终特性会受到怎样的影响。在这里，我们整合了描述过表达Dyrk1A（TgDyrk1A）的转基因小鼠前额叶网络改变的功能、解剖和计算数据。通过体内细胞外记录，我们发现麻醉和清醒的TgDyrk1A小鼠前额叶网络的放电率和γ频率功率降低。免疫组织化学分析表明，小清蛋白阳性神经元上的囊泡GABA转运体斑点选择性减少，而TgDyrk1A小鼠PFC中皮质GABA能神经元的数量没有变化，这表明小清蛋白中间神经元的选择性去抑制会导致功能网络过度抑制。使用基于电导的计算模型，我们定量证明这种改变可以解释观察到的功能缺陷，包括γ功率和放电率降低。我们的结果表明，皮质快速放电中间神经元功能障碍可能是唐氏综合征病理生理学的核心。
DYRK1A是唐氏综合征的主要候选基因。其过表达导致认知能力改变，这可以通过皮质微结构缺陷和兴奋/抑制失衡来解释。一个悬而未决的问题是这些缺陷如何影响前额叶皮层网络的功能。结合功能、解剖和计算方法，我们发现过表达Dyrk1A的转基因小鼠前额叶皮层的神经元放电率降低和γ频率缺陷。我们还发现小清蛋白阳性中间神经元上的囊泡GABA转运体斑点特异性减少。使用基于电导的计算模型，我们证明中间神经元上这种抑制作用的降低概括了观察到的功能缺陷，包括γ功率和放电率降低。我们的结果表明，皮质快速放电中间神经元功能障碍可能是唐氏综合征病理生理学的核心。
