GABAB receptor-mediated feed-forward circuit dysfunction in the mouse model of fragile X syndrome

Sarah Wahlstrom-Helgren, Vitaly A. Klyachko

Research output: Contribution to journalArticlepeer-review

17 Scopus citations


Circuit hyperexcitability has been implicated in neuropathology of fragile X syndrome, the most common inheritable cause of intellectual disability. Yet, how canonical unitary circuits are affected in this disorder remains poorly understood. Here, we examined this question in the context of the canonical feed-forward inhibitory circuit formed by the temporoammonic (TA) branch of the perforant path, the major cortical input to the hippocampus. TA feed-forward circuits exhibited a marked increase in excitation/inhibition ratio and major functional defects in spike modulation tasks in Fmr1 knock-out (KO) mice, a fragile X mouse model. Changes in feed-forward circuits were caused specifically by inhibitory, but not excitatory, synapse defects. TA-associated inhibitory synapses exhibited increase in paired-pulse ratio and in the coefficient of variation of IPSPs, consistent with decreased GABA release probability. TA-associated inhibitory synaptic transmission in Fmr1 KO mice was also more sensitive to inhibition of GABAB receptors, suggesting an increase in presynaptic GABAB receptor (GABABR) signalling. Indeed, the differences in inhibitory synaptic transmission between Fmr1 KO and wild-type (WT) mice were eliminated by a GABABR antagonist. Inhibition of GABABRs or selective activation of presynaptic GABABRs also abolished the differences in the TA feed-forward circuit properties between Fmr1 KO and WT mice. These GABABR-mediated defects were circuit-specific and were not observed in the Schaffer collateral pathway-associated inhibitory synapses. Our results suggest that the inhibitory synapse dysfunction in the cortico-hippocampal pathway of Fmr1 KO mice causes hyperexcitability and feed-forward circuit defects, which are mediated in part by a presynaptic GABABR-dependent reduction in GABA release. Journal compilation

Original languageEnglish
Pages (from-to)5009-5024
Number of pages16
JournalJournal of Physiology
Issue number22
StatePublished - Nov 15 2015

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