Imbalance of neocortical excitation and inhibition and altered UP states reflect network hyperexcitability in the mouse model of fragile X syndrome.
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 ( approximately 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.
Gibson
Jay R
JR
Dept. of Neuroscience, University of Texas, Southwestern Medical Center, Box 9111, Dallas, TX 75390-9111, USA. Jay.Gibson@UTSouthwestern.edu
Bartley
Aundrea F
AF
Hays
Seth A
SA
Huber
Kimberly M
KM
D000200:Action Potentials / Q000235:genetics; D000818:Animals; D004195:Disease Models, Animal; D004558:Electric Stimulation / Q000379:methods; D005246:Feedback; D005260:Female; D051860:Fragile X Messenger Ribonucleoprotein 1 / Q000235:genetics; D005600:Fragile X Syndrome / Q000235:genetics / Q000473:pathology* / Q000503:physiopathology*; D049452:Green Fluorescent Proteins / Q000096:biosynthesis / Q000235:genetics; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D019579:Neocortex / Q000473:pathology*; D009415:Nerve Net / Q000473:pathology*; D009433:Neural Inhibition / Q000502:physiology*; D013569:Synapses / Q000187:drug effects / Q000502:physiology; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology / Q000528:radiation effects; D013788:Thalamus / Q000503:physiopathology
D051860:Fragile X Messenger Ribonucleoprotein 1; D049452:Green Fluorescent Proteins; C497684:Fmr1 protein, mouse
Cell. 1994 Nov 18;79(4):717-27
7954835
Am J Med Genet. 1991 Feb-Mar;38(2-3):283-7
2018072
Neuron. 2007 Jun 21;54(6):919-31
17582332
J Neurosci. 2006 Jul 5;26(27):7151-5
16822971
Proc Natl Acad Sci U S A. 2002 May 28;99(11):7746-50
12032354
Neuron. 2001 Aug 16;31(3):477-85
11516403
J Cereb Blood Flow Metab. 1990 Jan;10(1):136-9
2404997
Cereb Cortex. 2000 Oct;10(10):1045-52
11007555
J Physiol. 2005 Jan 15;562(Pt 2):569-82
15528249
Curr Opin Psychiatry. 2005 Sep;18(5):490-6
16639106
Neuroscience. 1991;41(2-3):365-79
1870696
J Neurosci. 2005 Oct 12;25(41):9460-9
16221856
Epilepsia. 2000 Jan;41(1):19-23
10643918
J Neurosci. 2000 May 1;20(9):3354-68
10777798
Am J Med Genet. 1999 Apr 2;83(4):268-79
10208160
Cell. 2001 Nov 16;107(4):489-99
11719189
Neuron. 2005 Dec 8;48(5):811-23
16337918
Genes Brain Behav. 2006 Aug;5(6):467-71
16923151
Mol Cell Neurosci. 2002 Feb;19(2):138-51
11860268
Neurobiol Dis. 2006 Feb;21(2):346-57
16199166
Nat Neurosci. 2006 Jan;9(1):99-107
16369481
Brain Topogr. 2003 Spring;15(3):165-71
12705812
Mol Psychiatry. 2004 Apr;9(4):417-25
14981523
Curr Opin Neurobiol. 2001 Aug;11(4):488-97
11502397
Nat Rev Neurosci. 2005 Nov;6(11):877-88
16261181
Cell. 2001 Nov 30;107(5):591-603
11733059
Hum Mol Genet. 2006 Jun 15;15(12):1984-94
16675531
Genes Brain Behav. 2005 Oct;4(7):420-30
16176388
Cereb Cortex. 2000 Oct;10(10):1038-44
11007554
Cereb Cortex. 1997 Sep;7(6):583-604
9276182
Nature. 2006 Nov 30;444(7119):610-3
17086200
Nature. 1996 Oct 17;383(6601):621-4
8857537
J Neurophysiol. 2007 Jun;97(6):4186-202
17409168
J Neurosci. 2005 Aug 31;25(35):8048-55
16135762
Proc Natl Acad Sci U S A. 2005 Aug 30;102(35):12560-5
16116096
J Neurosci. 2005 Jan 26;25(4):1024-33
15673684
Trends Neurosci. 1990 Mar;13(3):99-104
1691879
Nature. 1999 Jul 22;400(6742):367-71
10432115
Cereb Cortex. 1997 Jun;7(4):347-58
9177765
J Neurosci. 2007 Apr 11;27(15):4014-8
17428978
Biol Psychiatry. 2007 Aug 1;62(3):192-7
16950225
J Comp Neurol. 1987 Aug 1;262(1):1-12
3305602
Nature. 2003 May 15;423(6937):288-93
12748642
J Neurosci. 2006 Jan 25;26(4):1219-30
16436609
Proc Natl Acad Sci U S A. 2007 Feb 13;104(7):2454-9
17287348
J Neurophysiol. 2006 Oct;96(4):1734-45
16823030
Am J Med Genet A. 2004 Sep 1;129A(3):225-34
15326621
J Neurophysiol. 1999 Nov;82(5):2476-89
10561420
Neuron. 2006 Oct 5;52(1):155-68
17015233
Curr Biol. 2004 Oct 26;14(20):1863-70
15498496
J Neurosci. 1997 May 15;17(10):3894-906
9133407
Nature. 1999 Nov 4;402(6757):75-9
10573419
Brain Res. 2002 Feb 8;927(1):8-17
11814427
Seizure. 2001 Jan;10(1):60-3
11181100
Science. 1993 Oct 29;262(5134):679-85
8235588
Trends Neurosci. 2003 Dec;26(12):676-82
14624852
J Neurosci. 2007 Apr 18;27(16):4261-72
17442810
J Neurosci. 2007 Mar 21;27(12):3120-30
17376973
Neuron. 2007 Feb 15;53(4):591-604
17296559
J Neurosci. 2008 May 14;28(20):5178-88
18480274
Cell. 1994 Jul 15;78(1):23-33
8033209
Neuroreport. 2001 Aug 8;12(11):2573-6
11496151
Nature. 2003 May 15;423(6937):283-8
12748641
J Neurosci. 1997 Mar 1;17(5):1539-47
9030614
J Dev Behav Pediatr. 2001 Dec;22(6):409-17
11773805
Dev Med Child Neurol. 2002 Nov;44(11):724-8
12418611
Epilepsia. 1999 Aug;40(8):1092-9
10448821
Nature. 1999 Nov 4;402(6757):72-5
10573418
J Neurosci. 2005 Aug 10;25(32):7385-92
16093389
Nat Neurosci. 1998 Aug;1(4):279-85
10195160
J Comput Neurosci. 2001 Jul-Aug;11(1):63-85
11524578
Brain Res Brain Res Rev. 1998 May;26(2-3):113-35
9651498
Neuron. 2005 Feb 17;45(4):563-73
15721242
Nat Neurosci. 2006 May;9(5):608-10
16617340
Nat Neurosci. 2000 Oct;3(10):1027-34
11017176
Neurosci Lett. 2007 Feb 2;412(3):227-32
17197085
Neurosci Lett. 2005 Apr 4;377(3):141-6
15755515
Neuron. 2005 Aug 4;47(3):423-35
16055065
Neuron. 1996 Apr;16(4):815-23
8607999
Brain Dev. 2002 Dec;24(8):766-9
12453600
Bull Tokyo Med Dent Univ. 1986 Mar;33(1):1-8
3457643
Neuroscience. 2001;103(4):1043-50
11301211
Science. 2001 Jun 22;292(5525):2295-9
11423653
Neuron. 2004 Jun 24;42(6):889-96
15207234
Cell. 1991 May 31;65(5):905-14
1710175
Annu Rev Neurosci. 2002;25:315-38
12052912
J Neurophysiol. 2005 Jan;93(1):467-80
15317837
Microsc Res Tech. 2002 May 1;57(3):174-8
12112454
Genes Brain Behav. 2003 Oct;2(5):255-67
14606691