Abnormal striatal GABA transmission in the mouse model for the fragile X syndrome.
BACKGROUND
Structural and functional neuroimaging studies suggest abnormal activity in the striatum of patients with the fragile X syndrome (FXS), the most common form of inherited mental retardation.


METHODS
Neurophysiological and immunofluorescence experiments in striatal brain slices. We studied the synaptic transmission in a mouse model for FXS, as well as the subcellular localization of fragile X mental retardation protein (FMRP) and brain cytoplasmic (BC1) RNA in striatal axons.


RESULTS
Our results show that absence of FMRP is associated with apparently normal striatal glutamate-mediated transmission, but abnormal gamma-aminobutyric acid (GABA) transmission. This effect is likely secondary to increased transmitter release from GABAergic nerve terminals. We detected the presence of FMRP in axons of striatal neurons and observed a selective increase in the frequency of spontaneous and miniature inhibitory postsynaptic currents (sIPSCs, mIPSCs) in fmr1-knockout mice. We also observed reduced paired-pulse ratio of evoked IPSCs, a finding that is consistent with the idea that transmitter release probability from striatal GABAergic nerve terminals is higher than normal in these mutants. Finally, we have identified the small noncoding BC1 RNA as a critical coplayer of FMRP in the regulation of striatal synaptic transmission.


CONCLUSIONS
Understanding the physiologic action of FMRP and the synaptic defects associated with GABA transmission might be useful to design appropriate pharmacologic interventions for FXS.
Centonze
Diego
D
Clinica Neurologica, Dipartimento di Neuroscienze, Università Tor Vergata, Rome, Italy. centonze@uniroma2.it
Rossi
Silvia
S
Mercaldo
Valentina
V
Napoli
Ilaria
I
Ciotti
Maria Teresa
MT
De Chiara
Valentina
V
Musella
Alessandra
A
Prosperetti
Chiara
C
Calabresi
Paolo
P
Bernardi
Giorgio
G
Bagni
Claudia
C
D000818:Animals; D002540:Cerebral Cortex / Q000473:pathology / Q000503:physiopathology; D003342:Corpus Striatum / Q000378:metabolism* / Q000473:pathology; D004195:Disease Models, Animal; D004558:Electric Stimulation / Q000379:methods; D051860:Fragile X Messenger Ribonucleoprotein 1 / Q000235:genetics / Q000378:metabolism; D005600:Fragile X Syndrome / Q000235:genetics / Q000473:pathology* / Q000503:physiopathology*; D005786:Gene Expression Regulation / Q000235:genetics; D066298:In Vitro Techniques; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009433:Neural Inhibition / Q000235:genetics / Q000528:radiation effects; D018408:Patch-Clamp Techniques / Q000379:methods; D010590:Phalloidine / Q000378:metabolism; D062085:RNA, Long Noncoding; D022661:RNA, Untranslated; D020736:Ribonucleoproteins, Small Cytoplasmic / Q000172:deficiency; D009435:Synaptic Transmission / Q000235:genetics / Q000502:physiology*; D050495:Vesicular Inhibitory Amino Acid Transport Proteins / Q000378:metabolism; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*
D051860:Fragile X Messenger Ribonucleoprotein 1; D010590:Phalloidine; D062085:RNA, Long Noncoding; D022661:RNA, Untranslated; D020736:Ribonucleoproteins, Small Cytoplasmic; D050495:Vesicular Inhibitory Amino Acid Transport Proteins; D005680:gamma-Aminobutyric Acid; C076675:Bc1 long-non-coding RNA, mouse; C497684:Fmr1 protein, mouse; C492244:Viaat protein, mouse