Elsevier

Biological Psychiatry

Volume 63, Issue 10, 15 May 2008, Pages 963-973
Biological Psychiatry

Original Article
Abnormal Striatal GABA Transmission in the Mouse Model for the Fragile X Syndrome

https://doi.org/10.1016/j.biopsych.2007.09.008Get rights and content

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 γ-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.

Section snippets

Methods and Materials

Mice lacking fmr1 (fmr1-KO) (34), BC1 RNA (BC1-KO) (35), and both fmr1 and BC1 (fmr1-BC1-KO) were employed, along with respective age-matched wildtype (WT) counterparts (2–3 months old) for all the experiments. Animals were maintained in light:dark cycles of 12:12 hours and weaned after 21 days. The WT and KO mice used in these experiments were of different background strains: C57BL/6 for fmr1-KO mice, 129Sv/C57BL/6 for BC1-KO and fmr1-BC1-KO. Appropriate matching strains were used as controls.

Membrane Properties of Striatal Neurons

Whole-cell patch clamp recordings were obtained from striatal spiny neurons identified by morphologic and electrophysiologic criteria. Striatal spiny neurons had significantly smaller somata than interneurons (15–25 μm vs. 30–40 μm) and displayed high resting membrane potential (–81 ± 4 mV), action potential discharge with little adaptation during depolarizing current pulses, and, in voltage-clamp mode, a typical current-voltage relationship. These electrophysiologic properties were similar in

Discussion

Reduced expression of FMRP in FXS patients causes a wide range of neuropsychiatric manifestations, which include mental retardation, hyperactivity, and autism (27, 50, 51, 52). Abnormal activity of striatal neurons and frontostriatal projections seem to play critical roles in FXS, as suggested by structural and functional neuroimaging studies. Accordingly, larger than normal caudate nucleus volumes have been found in human FXS brains, and a clear association between reduced FMRP expression,

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    This work is an equal contribution between the labs of Drs. Bagni and Centonze.

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