Imbalance of Neocortical Excitation and Inhibition and Altered UP States Reflect Network Hyperexcitability in the Mouse Model of Fragile X Syndrome

Journal of Neurophysiology - Tập 100 Số 5 - Trang 2615-2626 - 2008
Jay R. Gibson1, Aundrea F. Bartley2, Seth A. Hays2, Kimberly M. Huber1
1Neuroscience,
2University of Texas Southwestern Medical Center

Tóm tắt

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 (∼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.

Từ khóa


Tài liệu tham khảo

10.1016/0306-4522(91)90333-J

Bakker DB. Fmr1 knockout mice: a model to study fragile X mental retardation. The Dutch-Belgian Fragile X Consortium. Cell 78: 23–33, 1994.

10.1111/j.1469-8749.2002.tb00277.x

10.1093/cercor/10.10.1045

10.1111/j.1601-183X.2005.00183.x

10.1023/A:1011204814320

10.1523/JNEUROSCI.1076-08.2008

10.1016/j.neuron.2004.05.014

10.1023/A:1022606200636

10.1523/JNEUROSCI.17-10-03894.1997

10.1016/S0306-4522(01)00036-7

10.1523/JNEUROSCI.1777-05.2005

10.1016/j.neuron.2007.05.029

10.1016/0166-2236(90)90185-D

10.1038/nature01614

10.1038/nn1690

10.1073/pnas.0506071102

10.1016/S0092-8674(01)00566-9

10.1016/S0896-6273(01)00373-7

10.1152/jn.00221.2006

10.1016/j.neulet.2004.11.087

10.1152/jn.1999.82.5.2476

10.1523/JNEUROSCI.17-05-01539.1997

10.1038/22553

10.1038/sj.mp.4001432

10.1016/j.neuron.2007.01.031

10.1038/47029

10.1126/science.1061395

10.1016/j.nbd.2005.07.017

10.1016/0092-8674(94)90556-8

10.1152/jn.00520.2004

10.1038/47035

10.1093/cercor/7.4.347

10.1523/JNEUROSCI.1790-06.2006

Hagerman R. The physical and behavioral phenotype. In: Fragile X Syndrome: Diagnosis, Treatment, and Research, edited by Hagerman R, and Hagerman P. Baltimore, MD: The Johns Hopkins University Press, 2002, p. 3–109.

10.1002/ajmg.1320380223

10.1097/01.yco.0000179485.39520.b0

10.1152/jn.01114.2006

10.1523/JNEUROSCI.4717-06.2007

10.1016/j.neuron.2005.06.016

10.1038/nrn1787

10.1073/pnas.122205699

10.1016/S0387-7604(02)00102-X

10.1093/cercor/10.10.1038

10.1002/jemt.10069

Kaufmann WE, Cortell R, Kau AS, Bukelis I, Tierney E, Gray RM, Cox C, Capone GT, Stanard P. Autism spectrum disorder in fragile X syndrome: communication, social interaction, and specific behaviors. Am J Med Genet A 129: 225–234, 2004.

10.1002/cne.902620102

10.1523/JNEUROSCI.2638-05.2005

10.1006/mcne.2001.1085

10.1016/j.neuron.2005.09.035

10.1038/nature05278

10.1016/S0896-6273(00)80101-4

10.1016/S0959-4388(00)00239-7

10.1002/(SICI)1096-8628(19990402)83:4<268::AID-AJMG7>3.0.CO;2-K

10.1111/j.1528-1157.2000.tb01499.x

10.1111/j.1528-1157.1999.tb00824.x

10.1016/S0006-8993(01)03309-1

10.1146/annurev.neuro.25.112701.142909

10.1523/JNEUROSCI.20-09-03354.2000

10.1016/j.cub.2004.09.085

10.1523/JNEUROSCI.0054-07.2007

10.1038/1092

10.1523/JNEUROSCI.0003-07.2007

10.1097/00004703-200112000-00008

10.1097/00001756-200108080-00056

10.1113/jphysiol.2004.071381

10.1034/j.1601-183X.2003.00037.x

10.1053/seiz.2000.0492

10.1038/79848

10.1016/j.neuron.2004.12.056

10.1016/j.neulet.2006.11.062

10.1038/nature01616

10.1016/S0165-0173(97)00061-1

10.1111/j.1601-183X.2005.00123.x

10.1093/hmg/ddl121

10.1093/cercor/7.6.583

10.1126/science.8235588

10.1038/nn1618

10.1523/JNEUROSCI.4727-04.2006

10.1038/383621a0

10.1016/j.neuron.2006.09.020

10.1016/0092-8674(91)90397-H

10.1523/JNEUROSCI.3951-04.2005

10.1016/j.tins.2003.09.016

10.1073/pnas.0610875104

10.1016/j.biopsych.2006.07.002

Yamaguchi T. Cerebral extracellular potassium concentration change and cerebral impedance change in short-term ischemia in gerbil. Bull Tokyo Med Dent Univ 33: 1–8, 1986.

10.1038/jcbfm.1990.18

10.1016/S0092-8674(01)00589-X

10.1523/JNEUROSCI.1520-05.2005

Thông tin
Thông tin xuất bản

Journal of Neurophysiology

Tập 100 Số 5

2615-2626

Thông tin tác giả