title: Increased long-term potentiation at medial-perforant path-dentate granule cell synapses induced by selective inhibition of histone deacetylase 3 requires Fragile X mental retardation protein.
abstract: Non-selective inhibition of histone deacetylases (HDACs), enzymes that remove acetyl groups from histone core proteins, enhances cognition and NMDAR-dependent long-term potentiation at hippocampal CA3-CA1 synapses. It is not known whether this is a general mechanism by which HDACs modulate plasticity at other hippocampal synapses. Furthermore, it has yet to be tested whether HDAC inhibition can reverse deficits in synaptic plasticity in disease models. Here, we investigated whether inhibition of HDACs, and specifically HDAC3, a class I HDAC isoform known to negatively regulate hippocampus-dependent learning and memory, enhances LTP at medial perforant path-dentate granule cell (MPP-DGC) synapses in wild-type and Fragile X (Fmr1-/y) mice, a model with known LTP deficits at this synapse. The non-selective HDAC inhibitor trichostatin A (TSA) significantly increased the magnitude of LTP at MPP-DGC synapses in wild-type mice, similar to reports at CA3-CA1 synapses. The enhancement of LTP was mimicked by selective HDAC3 inhibition, implicating a role for this isoform in the negative regulation of synaptic plasticity. However, HDAC3 inhibition was completely ineffective in reversing the deficit in LTP at MPP-DGC synapses in slices from Fmr1-/y mice, and in fact, HDAC3 inhibition was unable to induce any improvement whatsoever. These findings indicate that the enhancing effect of HDAC3 inhibition on LTP in wild-type mice requires FMRP, revealing a novel role for FMRP in hippocampal plasticity.
authors: Cell, Developmental and Integrative Biology, University of Alabama at Birmingham, 1918 University Blvd, MCLM 960, Birmingham, AL 35294, United States. Electronic address: alvinson@uab.edu.
authors: Aimee V
authors: AV
authors: Franklin
authors: Repligen Corporation, 41 Seyon Street, Building #1, Waltham, MA 02453, United States. Electronic address: jrusche@repligen.com.
authors: James R
authors: JR
authors: Rusche
authors: Cell, Developmental and Integrative Biology, University of Alabama at Birmingham, 1918 University Blvd, MCLM 960, Birmingham, AL 35294, United States. Electronic address: mcmahon@uab.edu.
authors: Lori L
authors: LL
authors: McMahon
mesh_terms: D000818:Animals; D018891:Dentate Gyrus / Q000187:drug effects / Q000502:physiology*; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000502:physiology; D051860:Fragile X Messenger Ribonucleoprotein 1 / Q000235:genetics* / Q000378:metabolism; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006655:Histone Deacetylases / Q000378:metabolism; D017774:Long-Term Potentiation / Q000187:drug effects / Q000502:physiology*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009474:Neurons / Q000187:drug effects / Q000502:physiology; D019580:Perforant Pathway / Q000187:drug effects / Q000502:physiology*; D013569:Synapses / Q000187:drug effects / Q000502:physiology*; D000099186:Histone Deacetylase 3
chemical_list: D051860:Fragile X Messenger Ribonucleoprotein 1; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases; D000099186:Histone Deacetylase 3
keywords: Excitatory transmission; Hippocampus; Mental retardation; Plasticity