Defective GABAergic neurotransmission and pharmacological rescue of neuronal hyperexcitability in the amygdala in a mouse model of fragile X syndrome - PubMed (original) (raw)

Phasic and tonic inhibition are impaired in Fmr1 KO mice. A1, B1, Current-clamp traces identifying cells from WT (A1) and Fmr1 KOs (B1) as excitatory principal neurons. Repetitive AP firing in response to a 40 pA depolarizing current step is shown. A2, B2, Continuous voltage-clamp traces from the above cells showing sIPSCs recorded from these same cells in the presence of APV (50 μ

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) and DNQX (20 μ

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). C, Overlay of averaged sIPSCs from cells in A1–B2. D–G, Averaged group data, showing reductions in sIPSC and mIPSC frequency (D), amplitude (E), and inhibitory efficacy (G), as well as a significant prolongation of sIPSC weighted tau (F). Note the similarity between frequency of mIPSCs in WT and sIPSCs in Fmr1 KOs. These differences were not related to differences in intrinsic membrane properties (_V_m: WT, −61.1 ± 0.7 mV; Fmr1 KO, −60.7 ± 0.8 mV; p = 0.95; _R_m: WT, 223 ± 13 MΩ; Fmr1 KO, 217 ± 13 MΩ; p = 0.55). H, I, Voltage-clamp traces from representative WT and Fmr1 KO principal neurons (_V_hold = −60 mV) indicating the difference between the average baseline holding current and average holding current in locally applied 100 μ

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Gabazine, as determined by fitted Gaussian curve (see Materials and Methods). J, Total inhibitory tonic current is significantly reduced in Fmr1 KO principal neurons. K, Voltage-clamp trace from a WT principal neuron illustrating its AP-dependent tonic GABAergic current and total tonic current. L, Averaged group data, showing that the primary source of tonic inhibitory current in both WT and Fmr1 KO principal neurons is AP-dependent GABA release. *p < 0.05; ***p < 0.005. Calibration: A1, B1, 20 mV, 200 ms; A2, B2, 100 pA, 500 ms; C, 20 pA, 20 ms; H, I, 20 pA, 5 s; K, 10 pA, 5 s.