New Publication by the Klyachko Lab
Congratulations to Sarah Wahlstrom-Helgren and Vitaly Klyachko on their new publication in the Journal of Physiology!
Wahlstrom-Helgren, S and Klyachko, VA (2015) GABAB Receptor-mediated feed-forward circuit dysfunction in the mouse model of Fragile X syndrome. J. Physiol. [E-published August 18] doi: 10.1113/JP271190.
Abstract: 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/excitation ratio and major functional defects in spike modulation tasks in Fmr1 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 (GABAB R) signaling. Indeed, the differences in inhibitory synaptic transmission between Fmr1 KO and WT mice were eliminated by a GABAB R antagonist. Inhibition of GABAB Rs or selective activation of presynaptic GABAB Rs also abolished the differences in the TA feed-forward circuit properties between Fmr1 KO and WT mice. These GABAB R-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 cortical-hippocampal pathway of Fmr1 KO mice causes hyperexcitability and feed-forward circuit defects, which are mediated in part by a presynaptic GABAB R-dependent reduction in GABA release. This article is protected by copyright. All rights reserved.