Imbalance of Neocortical Excitation and Inhibition and Altered UP States Reflect Network Hyperexcitability in the Mouse Model of Fragile X Syndrome
Imbalance of Neocortical Excitation and Inhibition and Altered UP States Reflect Network Hyperexcitability in the Mouse Model of Fragile X Syndrome
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DOI：
10.1152/jn.90752.2008
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发表时间：
2008-11-01
影响因子：
2.5
通讯作者：
Huber, Kimberly M.
中科院分区：
文献类型：
--
作者：
Gibson, Jay R.;Bartley, Aundrea F.;Huber, Kimberly M.
小吉布森，巴特利，海斯，S，胡贝尔·公里。在脆性X综合征小鼠模型中，新皮质兴奋和抑制的失衡以及向上状态的改变反映了网络的过度兴奋。神经生理学杂志100：2615-2626,2008。2008年9月10日首次出版；DOI：10.1152/jn.90752.2008。尽管与智力低下和自闭症相关的明显的神经缺陷，但在这些普遍存在的疾病中是否存在新皮质回路功能的改变尚不清楚。在这里，我们展示了脆性X综合征小鼠模型-Fmr1基因敲除(KO)-在感觉新皮质中特定类型神经元的局部突触连接、膜兴奋性和电路活动的特定变化。总体而言，这些改变导致Fmr1KO中新皮质回路的过度兴奋性。具体地说，我们观察到在针对躯体感觉第四层桶状皮质的快峰(FS)抑制神经元的局部兴奋驱动(类似于50%)方面存在重大缺陷。这种情况至少会持续到4周大，这表明它可能是永久性的。相反，单突触GABA能突触传递不受影响。总体而言，这些变化表明Fmr1KO小鼠新皮质第四层的局部反馈抑制严重受损。兴奋性神经元固有膜兴奋性的增加可能进一步促进皮层网络的过度兴奋性。为了支持这一观点，在Fmr1KO小鼠中，丘脑刺激引起的持续性新皮质回路活动或UP状态持续时间更长。此外，在正常状态下，网络抑制的同步性较弱，包括伽马频率范围(30-80赫兹)的同步性降低了14%。这些回路的改变可能与感觉刺激过敏、癫痫以及与脆性X和自闭症相关的认知障碍有关。
Gibson JR, Bartley AF, Hays S, Huber KM. Imbalance of neocortical excitation and inhibition and altered UP states reflect network hyperexcitability in the mouse model of Fragile X Syndrome. J Neurophysiol 100: 2615-2626, 2008. First published September 10, 2008; doi:10.1152/jn.90752.2008. Despite the pronounced neurological deficits associated with mental retardation and autism, it is unknown if altered neocortical circuit function occurs in these prevalent disorders. Here we demonstrate specific alterations in local synaptic connections, membrane excitability, and circuit activity of defined neuron types in sensory neocortex of the mouse model of Fragile X Syndrome-the Fmr1 knockout (KO). Overall, these alterations result in hyperexcitability of neocortical circuits in the Fmr1 KO. Specifically, we observe a substantial deficit in local excitatory drive (similar to 50%) targeting fast-spiking (FS) inhibitory neurons in layer 4 of somatosensory, barrel cortex. This persists until at least 4 wk of age suggesting it may be permanent. In contrast, monosynaptic GABAergic synaptic transmission was unaffected. Overall, these changes indicate that local feedback inhibition in neocortical layer 4 is severely impaired in the Fmr1 KO mouse. An increase in the intrinsic membrane excitability of excitatory neurons may further contribute to hyperexcitability of cortical networks. In support of this idea, persistent neocortical circuit activity, or UP states, elicited by thalamic stimulation was longer in duration in the Fmr1 KO mouse. In addition, network inhibition during the UP state was less synchronous, including a 14% decrease in synchrony in the gamma frequency range (30-80 Hz). These circuit changes may be involved in sensory stimulus hypersensitivity, epilepsy, and cognitive impairment associated with Fragile X and autism.