Alterations in cortical excitation and inhibition in genetic mouse models of Huntington's disease.
Previously, we identified progressive alterations in spontaneous EPSCs and IPSCs in the striatum of the R6/2 mouse model of Huntington's disease (HD). Medium-sized spiny neurons from these mice displayed a lower frequency of EPSCs, and a population of cells exhibited an increased frequency of IPSCs beginning at approximately 40 d, a time point when the overt behavioral phenotype begins. The cortex provides the major excitatory drive to the striatum and is affected during disease progression. We examined spontaneous EPSCs and IPSCs of somatosensory cortical pyramidal neurons in layers II/III in slices from three different mouse models of HD: the R6/2, the YAC128, and the CAG140 knock-in. Results revealed that spontaneous EPSCs occurred at a higher frequency, and evoked EPSCs were larger in behaviorally phenotypic mice whereas spontaneous IPSCs were initially increased in frequency in all models and subsequently decreased in R6/2 mice after they displayed the typical R6/2 overt behavioral phenotype. Changes in miniature IPSCs and evoked IPSC paired-pulse ratios suggested altered probability of GABA release. Also, in R6/2 mice, blockade of GABA(A) receptors induced complex discharges in slices and seizures in vivo at all ages. In conclusion, altered excitatory and inhibitory inputs to pyramidal neurons in the cortex in HD appear to be a prevailing deficit throughout the development of the disease. Furthermore, the differences between synaptic phenotypes in cortex and striatum are important for the development of future therapeutic approaches, which may need to be targeted early in the development of the phenotype.
Cummings
Damian M
DM
Mental Retardation Research Center, David Geffen School of Medicine, Semel Institute for Neuroscience and Human Behavior, University of California at Los Angeles, Los Angeles, CA 90095, USA.
André
Véronique M
VM
Uzgil
Besim O
BO
Gee
Steven M
SM
Fisher
Yvette E
YE
Cepeda
Carlos
C
Levine
Michael S
MS
D000818:Animals; D002540:Cerebral Cortex / Q000502:physiology*; D004195:Disease Models, Animal; D005260:Female; D006816:Huntington Disease / Q000235:genetics* / Q000503:physiopathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D008822:Mice, Transgenic; D009433:Neural Inhibition / Q000502:physiology*; D017966:Pyramidal Cells / Q000502:physiology; D055366:Synaptic Potentials / Q000502:physiology*
J Neurosci. 1999 Dec 1;19(23):10428-37
10575040
Brain Res Bull. 2007 Apr 30;72(2-3):103-7
17352933
Mol Cell Neurosci. 2002 Aug;20(4):638-48
12213445
Hum Mol Genet. 2006 May 15;15(10):1690-703
16600988
J Neurosci. 1995 Jun;15(6):4449-63
7790919
Science. 1985 Nov 1;230(4725):561-3
2931802
Scand J Psychol. 2001 Jul;42(3):287-96
11501742
Acta Psychiatr Scand. 2002 Mar;105(3):224-30
11939977
J Neurosci Res. 2004 Dec 15;78(6):855-67
15505789
Brain Res Bull. 2007 Apr 30;72(2-3):83-97
17352931
J Neurophysiol. 2001 Dec;86(6):2667-77
11731527
Eur J Pharmacol. 2002 Sep 13;451(2):103-10
12231378
J Neurosci. 2000 Mar 15;20(6):2202-8
10704495
J Neurosci Res. 2005 Nov 1;82(3):377-86
16211559
Annu Rev Neurosci. 1989;12:13-31
2648947
J Neurophysiol. 1989 Dec;62(6):1280-6
2600625
Brain Res Bull. 2001 Sep 15;56(2):111-7
11704347
Exp Brain Res. 1998 May;120(1):70-84
9628405
J Neurosci Res. 2001 Nov 15;66(4):525-39
11746372
Hum Mol Genet. 2006 Oct 1;15(19):2856-68
16905556
Cell. 1996 Nov 1;87(3):493-506
8898202
J Comp Neurol. 2005 Oct 3;490(4):354-70
16127709
Trends Neurosci. 2004 Nov;27(11):691-7
15474170
Nat Rev Neurosci. 2004 Oct;5(10):793-807
15378039
Neurology. 2001 Aug 28;57(4):708-11
11524486
Neurology. 2005 Sep 13;65(5):745-7
16157910
Neuron. 2004 Dec 16;44(6):977-86
15603740
Eur J Pediatr. 2004 Dec;163(12):717-21
15338298
Hum Mol Genet. 2006 Mar 15;15(6):965-77
16467349
Prog Neurobiol. 2007 Apr;81(5-6):253-71
17169479
Hum Mol Genet. 2003 Jul 1;12(13):1555-67
12812983
Mol Cell Neurosci. 2004 Mar;25(3):469-79
15033175
J Neurophysiol. 2005 May;93(5):2565-74
15625098
Proc Natl Acad Sci U S A. 1997 Mar 18;94(6):2665-70
9122253
Hum Mol Genet. 2003 Aug 15;12(16):2021-30
12913073
Neuroscience. 2008 Nov 11;157(1):280-95
18805465
J Neurophysiol. 2006 Apr;95(4):2108-19
16381805
Neurosci Lett. 2006 Dec 13;410(1):6-10
17070651
Neurosci Lett. 2004 Aug 26;367(1):1-5
15308285
Neuron. 2002 Mar 14;33(6):849-60
11906693
Mol Pharmacol. 1995 Nov;48(5):835-40
7476913
Proc Natl Acad Sci U S A. 2000 Jul 5;97(14):8093-7
10869421
Brain. 2008 Apr;131(Pt 4):1057-68
18337273
J Neurosci. 1999 Apr 15;19(8):3248-57
10191337
Proc Natl Acad Sci U S A. 2000 Mar 28;97(7):3562-6
10725369
Nature. 1990 Aug 23;346(6286):724-9
2167454
J Neurosci. 2003 Feb 1;23(3):961-9
12574425
J Neuropathol Exp Neurol. 1985 Nov;44(6):559-77
2932539
Neuron. 2005 May 5;46(3):433-44
15882643
Neurobiol Dis. 2008 Jun;30(3):293-302
18395459
J Neurosci. 2001 May 1;21(9):3009-16
11312285
Electroencephalogr Clin Neurophysiol. 1972 Mar;32(3):281-94
4110397
J Biol Chem. 2001 Oct 19;276(42):39271-6
11517213
Cell. 1993 Mar 26;72(6):971-83
8458085
J Neurol Neurosurg Psychiatry. 2008 Aug;79(8):874-80
18096682
Neuroscience. 2008 Dec 2;157(3):606-20
18854207
Mol Pharmacol. 1999 Mar;55(3):489-96
10051532
Exp Brain Res. 1994;101(2):272-8
7843313
J Neurosci Methods. 1988 Aug;25(1):1-11
3146670
J Comp Neurol. 2003 Oct 6;465(1):11-26
12926013
J Neurosci Res. 1999 Nov 15;58(4):515-32
10533044
Nature. 1990 Jul 12;346(6280):177-80
2164158
J Neurosci. 2007 Jul 18;27(29):7869-78
17634381
J Neurosci. 2000 Jul 1;20(13):5115-23
10864968