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 inhibiton 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.

Normal CA1 place fields but discoordinated network discharge in a Fmr1-null mouse model of fragile X syndrome

“…We began by examining synaptic function in the gene knockout Fmr1-null mouse using ex vivo hippocampal slice physiology. In agreement with prior work (Franklin et al, 2014;Godfraind et al, 1996;Hu et al, 2008;Lauterborn et al, 2007), we find that CA3 Schaffer collateral to CA1 synaptic efficacy and potentiation does not differ between WT and Fmr1-KO brain slices taken from task-naïve mice (Fig. 1).…”

“…However, the present findings appear incompatible with disruption hypotheses and strongly support alternative hyperstable/discoordination hypotheses for the consequences of FMRP loss in a neural circuit leading to intellectual disability in FXS. While we confirmed that Schaffer collateral synaptic transmission and plasticity are indistinguishable between naïve WT and Fmr1 KO brain slices as previously reported (Franklin et al, 2014;Godfraind et al, 1996;Hu et al, 2008;Lauterborn et al, 2007), we also uncovered substantial abnormalities in the mutant mice, but only after spatial experience (Fig. 1).…”

Deficits in synaptic function occur at medial perforant path-dentate granule cell synapses prior to Schaffer collateral-CA1 pyramidal cell synapses in the novel TgF344-Alzheimer's Disease Rat Model

“…Therefore, to determine whether heightened dendritic depolarization during LTP inducing stimulation might be linked with the increased LTP magnitude at MPP-DGC synapses, we assessed steady-state depolarization in 6 month TgF344-AD rats compared to WT littermate controls (Fig. 4), and analyzed this in two ways, as we have done previously (Franklin et al, 2014; Smith and McMahon, 2006). We measured the deflection from baseline at 170 msec after the stimulus artifiact when the deflection is stable, and also measured area under the curve (AUC).…”

Epigenetic regulation of the circadian gene Per1 contributes to age-related changes in hippocampal memory

“…Although this study clearly demonstrates that Per1 is an important gene through which HDAC3 regulates long-term memory in the aging brain, other genes most likely contribute to the memory-enhancing effects of HDAC3 deletion. Other genes proposed to mediate the effects of HDAC3 on synaptic plasticity and memory include NF-κB 34 , FMRP 37 , and Nr4a2 26 . In the current study, we identified an additional three genes (Fig.…”