Postnatal Loss of Mef2c Results in Dissociation of Effects on Synapse Number and Learning and Memory

Abstract

BACKGROUND Myocyte enhancer factor 2 (MEF2) transcription factors play critical roles in diverse cellular processes during CNS development. Studies attempting to address the role of MEF2 in brain have largely relied on overexpression of a constitutive MEF2 construct that impairs memory formation or knockdown of MEF2 function that increases spine numbers and enhances memory formation. Genetic deletion of individual MEF2 isoforms in brain during embryogenesis demonstrated Mef2c loss negatively regulates spine numbers resulting in learning and memory deficits, possibly due to its essential role in development. METHODS To further investigate Mef2c function in brain, we genetically deleted Mef2c during postnatal development in mice. We characterized these conditional Mef2c knockout mice in an array of behavioral paradigms and examined the impact of postnatal loss of Mef2c on long-term potentiation. RESULTS We observed increased spine numbers in hippocampus of the conditional Mef2c knockout mice. However, the postnatal loss of Mef2c did not impact learning and memory, long-term potentiation, or social and repetitive behaviors. CONCLUSIONS Our findings demonstrate a critical role for MEF2c in the regulation of spine numbers with a dissociation on learning and memory, synaptic plasticity and measures of autism-related behaviors in postnatal brain.

Experience-Dependent and Differential Regulation of Local and Long-Range Excitatory Neocortical Circuits by Postsynaptic Mef2c

“…Expression of a constitutively active MEF2C eliminates functional and structural excitatory synapses in cultured hippocampal neurons and in vivo (Cole et al, 2012; Flavell et al, 2006; Pfeiffer et al, 2010). Consistent with this finding, embryonic and postnatal deletion of Mef2c in forebrain results in increased excitatory synapse function and dendritic spines in vivo in granule cells of the hippocampal dentate gyrus (Adachi et al, 2015; Barbosa et al, 2008) and is necessary for synapse elimination in response to extracellular signals (Elmer et al, 2013). In contrast, embryonic brain wide deletion of Mef2c reduces synaptic strength onto CA1 and layer 5 neocortical neurons (Li et al, 2008).…”

“…Embryonic or postnatal brainwide deletion of Mef2c increases spine density and synaptic transmission onto dentate gyrus granule cells of the hippocampus (Adachi et al, 2015; Barbosa et al, 2008), while excitatory synaptic transmission is reduced in CA1 and onto L5 neurons (Barbosa et al, 2008). Because embryonic deletion of Mef2c also affects neuronal migration and gross laminarization of neocortex, the cell-autonomous and effects of Mef2c on synapse development and connectivity were unknown (Li et al, 2008).…”

Foxp2 controls synaptic wiring of corticostriatal circuits and vocal communication by opposing Mef2c

“…In the hippocampus, dendritic spine formation is negatively regulated by Mef2C in the dentate gyrus of hGFAP-Cre;Mef2C mice 21 , but not in the CA1 region of hGFAP-Cre;Mef2A;Mef2D double-knockout mice or hGFAP-Cre;Mef2A;Mef2C;Mef2D triple-knockout mice, apparently reflecting low Mef2C expression in the CA1 region 33 . Postnatal deletion of Mef2C also results in increased spines in the dentate gyrus in CaMKII-Cre;Mef2C knockout mice 34 .…”

MEF2C regulates cortical inhibitory and excitatory synapses and behaviors relevant to neurodevelopmental disorders

“…Loss of MEF2C in forebrain excitatory neurons produces an increase in structural and functional excitatory synapses formed onto hippocampal dentate granule neurons (DG) (Barbosa et al, 2008; Adachi et al, 2016), suggesting that MEF2C might have cell-type specific functions and/or that the increase in DG excitatory synaptic transmission is an indirect, homeostatic effect of decreased cortical stimulation of DG neurons. In the future, cell autonomous manipulations of the DG neurons will be important to resolve this question.…”

“…In the future, cell autonomous manipulations of the DG neurons will be important to resolve this question. Also, postnatal Mef2c deletion in forebrain excitatory neurons did not produce social or repetitive behavioral phenotypes, despite the increase in DG dendritic spine density (Adachi et al, 2016), suggesting a dissociation of hippocampal DG spine density and postnatal MEF2C deletion from several ASD-related behaviors. As such, the role(s) for MEF2C in embryonic and/or early postnatal cortical development might be more critical for producing the behavioral phenotypes observed in our Mef2c cKO mice.…”