Histone Deacetylases 1 and 2 Form a Developmental Switch That Controls Excitatory Synapse Maturation and Function

Abstract

The structural assembly of synapses can be accomplished in a rapid time frame, although most nascent synapses formed during early development are not fully functional and respond poorly to presynaptic action potentials. The mechanisms that are responsible for this delay in synapse maturation are unknown. Histone deacetylases (HDACs) regulate the activity state of chromatin and repress gene expression through the removal of acetyl groups from histones. Class I HDACs, which include HDAC1 and HDAC2, are expressed in the CNS, although their specific role in neuronal function has not been studied. To delineate the contribution of HDAC1 and HDAC2 in the brain, we have used pharmacological inhibitors of HDACs and mice with conditional alleles to HDAC1 and HDAC2. We found that a decrease in the activities of both HDAC1 and HDAC2 during early synaptic development causes a robust facilitation of excitatory synapse maturation and a modest increase in synapse numbers. In contrast, in mature neurons a decrease in HDAC2 levels alone was sufficient to attenuate basal excitatory neurotransmission without a significant change in the numbers of detectable nerve terminals. Therefore, we propose that HDAC1 and HDAC2 form a developmental switch that controls synapse maturation and function acting in a manner dependent on the maturational states of neuronal networks.

The Impact of MeCP2 Loss- or Gain-of-Function on Synaptic Plasticity

“…An important implication of this work is that MeCP2's effect on hippocampal spontaneous transmission appears to be due to its role as a transcriptional repressor . Moreover, we found that the impact of MeCP2 on the dynamics of evoked excitatory neurotransmission was similar to what is observed after loss of key histone deacetylases (histone deacetylase 1 and 2), enzymes that form a co-repressor complex with MeCP2 suggesting that alterations in transcriptional repression mediate the deficits in evoked synaptic activity (Akhtar et al, 2009). MeCP2 overexpression also impacts excitatory neurotransmission.…”

Histone deacetylases 1 and 2 are required for brain development

“…Interestingly, under the same conditions, HDAC activity does not impact inhibitory neurotransmission, which showed an over 50 fold increase over development, suggesting network specificity in the epigenetic control of synaptic circuits. Together, these results indicate that HDAC1 and 2 are critical regulators of excitation-inhibition balance in developing synaptic networks through their control of excitatory drive (Akhtar et al, 2009;Jawerka et al, 2010).…”

“…It is worth pointing out, that the roles of HDACs in control of excitatory synapse maturation and function are covered by Akhtar et al, (2009) and Guan et al, (2009) and will not be addressed in detail. Nevertheless, it is postulated that HDAC1 and HDAC2 form a developmental switch that controls excitatory synapse and function which is dependent on the maturational state of the neurons.…”

Mule determines the apoptotic response to HDAC inhibitors by targeted ubiquitination and destruction of HDAC2

“…Overexpression of HDAC2 leads to a strong inhibition of synaptogenesis and memory loss in affected animals (Akhtar et al 2009;Guan et al 2009). Coincidently, a homolog of Mule in Caenorhabditis elegans has also been isolated from a genetic screen as a crucial factor required for synaptogenesis in worms (Sieburth et al 2005).…”