Taurine regulation of short term synaptic plasticity in fragile X mice.
BACKGROUND
Fragile X Syndrome is the most common known genetic cause of autism. The Fmr1-KO mouse, lacks the fragile X mental retardation protein (FMRP), and is used as a model of the syndrome. The core behavioral deficits of autism may be conceptualized either as excessive adherence to patterns as seen in repetitive actions and aberrant language, or as insensitivity to subtle but socially important changes in patterns. The hippocampus receives information from the entorhinal cortex and plays a crucial role in the processing of patterned information. To gain more insight into the physiological function of FMRP and the neuronal mechanisms underlying fragile X syndrome, we examined the electrophysiological response of the hippocampus to pair pulse stimulation as a measure of patterned information processing and how it is affected in the Fmr1-KO mouse.


METHODS
In this study, we used paired-pulse stimulation of the afferent perforant path and recorded from the CA1 region of the hippocampus. Two-month-old FVB/NJ male mice and age-matched Fmr1-KO mice were used in this study. Hippocampal slices were prepared, equilibrated in artificial cerebrospinal fluid (aCSF), and excitatory post synaptic potentials (EPSPs) measured by stimulating the perforant path of the dentate gyrus (DG) while recording from the molecular layer of CA1. Stimulation occurred by setting current and pulse width to evoke a fixed percentage of maximal EPSP amplitude. This stimulation paradigm allowed us to examine the processing capabilities of the hippocampus as a function of increasing interstimulus intervals (ISI) and how taurine, a GABAA receptor agonist, affects such information processing.


RESULTS
We found that hippocampal slices from wild type (WT) showed pair-pulse facilitation at ISI of 100-300 ms whereas slices from Fmr1-KO brains showed a consistent pair-pulse depression at a comparable ISI. Addition of 10 muM taurine to WT slices resulted in a drastic decrease of the peak response to the second stimulus, resulting in an initial depression at 100 ms ISI followed by potentiation at higher ISI (150 ms and above). In the presence of taurine, the amplitude of the second response remained significantly lower than in its absence. Fmr1-KO mice however, were completely insensitive to taurine application and pair-pulse stimulation always resulted in a depression of the response to the second stimulus.


CONCLUSIONS
Previously we reported that Fmr1-KO mice have reduced beta subunits of the GABAA receptors. We also showed as well as others that taurine acts as an agonist or a modulator for GABAA receptors. Therefore, the insensitivity of Fmr1-KO slices to taurine application could be due to the reduced binding sites on the GABAA receptors in the Fmr1-KO mice.
El Idrissi
Abdeslem
A
Department of Biology, College of Staten Island, The City University of New York, 2800 Victory Boulevard, Staten Island, NY 10314, USA. Abdeslem.Elidrissi@csi.cuny.edu
Neuwirth
Lorenz S
LS
L'Amoreaux
William
W
D000818:Animals; D001665:Binding Sites; D004195:Disease Models, Animal; D004558:Electric Stimulation / Q000379:methods; D019706:Excitatory Postsynaptic Potentials / Q000502:physiology; D051860:Fragile X Messenger Ribonucleoprotein 1 / Q000235:genetics; D005600:Fragile X Syndrome / Q000503:physiopathology*; D006624:Hippocampus / Q000187:drug effects / Q000502:physiology*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009473:Neuronal Plasticity / Q000187:drug effects*; D019580:Perforant Pathway / Q000187:drug effects / Q000502:physiology; D021122:Protein Subunits / Q000235:genetics / Q000378:metabolism; D013654:Taurine / Q000008:administration & dosage / Q000494:pharmacology*
D051860:Fragile X Messenger Ribonucleoprotein 1; D021122:Protein Subunits; D013654:Taurine; C497684:Fmr1 protein, mouse
J Physiol. 1983 Mar;336:563-77
6135799
Am J Med Genet. 1991 Feb-Mar;38(2-3):476-80
2018089
Nucleic Acids Res. 2001 Jun 1;29(11):2276-83
11376146
J Neurosci. 2005 Aug 31;25(35):8048-55
16135762
J Physiol. 1996 Nov 15;497 ( Pt 1):145-59
8951718
Trends Neurosci. 2004 Jul;27(7):370-7
15219735
AAPS J. 2006 May 26;8(2):E353-61
16796386
Microsc Res Tech. 2002 May 1;57(3):168-73
12112453
Nat Med. 1995 Feb;1(2):159-67
7585014
Cell. 2001 Nov 16;107(4):477-87
11719188
Br J Pharmacol. 2003 Mar;138(6):1163-71
12684273
Am J Med Genet A. 2005 Jun 1;135(2):155-60
15880753
J Neurosci. 2008 Jan 2;28(1):106-15
18171928
J Physiol. 1997 Aug 1;502 ( Pt 3):609-21
9279812
J Physiol. 2005 Jun 1;565(Pt 2):503-16
15817633
Am J Med Genet. 1991 Dec 1;41(3):289-94
1724112
Proc Natl Acad Sci U S A. 2002 May 28;99(11):7746-50
12032354
Neurosci Res. 2008 Jul;61(3):302-8
18479770
Cereb Cortex. 2000 Oct;10(10):1045-52
11007555
Neuron. 2005 Aug 4;47(3):339-52
16055059
J Physiol. 2002 Feb 15;539(Pt 1):191-200
11850512
Neuron. 2003 Feb 6;37(3):417-31
12575950
J Neurosci. 1998 Oct 15;18(20):8505-14
9763493
Neurochem Res. 1986 Jan;11(1):85-94
3008015
J Neurosci. 2005 Oct 12;25(41):9460-9
16221856
Epilepsia. 2000 Jan;41(1):19-23
10643918
Genomics. 2002 Oct;80(4):423-32
12376097
Brain Res. 2000 May 12;864(2):298-307
10802037
Nat Neurosci. 2004 Feb;7(2):113-7
14703574
Neuroscience. 2001;104(4):1043-55
11457589
Am J Med Genet. 2001 Jan 15;98(2):161-7
11223852
Adv Exp Med Biol. 2009;643:191-8
19239149
Cell. 1994 Jul 15;78(1):23-33
8033209
Am J Med Genet. 1996 Aug 9;64(2):241-5
8844056
Br J Pharmacol. 2003 Jun;139(3):487-94
12788808
Neurosci Lett. 2007 Feb 2;412(3):227-32
17197085
Neurosci Lett. 2005 Apr 4;377(3):141-6
15755515
Cell. 1993 Jul 30;74(2):291-8
7688265
Curr Opin Genet Dev. 2002 Jun;12(3):284-93
12076671
Neuroscience. 2001;103(4):1043-50
11301211
J Neurosci. 2001 Jul 15;21(14):5139-46
11438589
Neuroscience. 1999;94(1):185-92
10613508
Am J Med Genet. 2002 Aug 1;111(2):140-6
12210340
Neurochem Res. 2004 Jan;29(1):189-97
14992278
Annu Rev Neurosci. 2002;25:315-38
12052912