The Transcription Factor MEF2 Directs Developmental Visually Driven Functional and Structural Metaplasticity

SummaryNatural sensory input shapes both structure and function of developing neurons, but how early experience-driven morphological and physiological plasticity are interrelated remains unclear. Using rapid time-lapse two-photon calcium imaging of network activity and single-neuron growth within the unanesthetized developing brain, we demonstrate that visual stimulation induces coordinated changes to neuronal responses and dendritogenesis. Further, we identify the transcription factor MEF2A/2D as a major regulator of neuronal response to plasticity-inducing stimuli directing both structural and functional changes. Unpatterned sensory stimuli that change plasticity thresholds induce rapid degradation of MEF2A/2D through a classical apoptotic pathway requiring NMDA receptors and caspases-9 and -3/7. Knockdown of MEF2A/2D alone is sufficient to induce a metaplastic shift in threshold of both functional and morphological plasticity. These findings demonstrate how sensory experience acting through altered levels of the transcription factor MEF2 fine-tunes the plasticity thresholds of brain neurons during neural circuit formation.

Graphical AbstractFigure optionsDownload full-size imageDownload high-quality image (290 K)Download as PowerPoint slideHighlights► The transcription factor MEF2 is a master regulator of developmental metaplasticity ► Developmental structural and functional neuronal plasticity are coordinated ► Unpatterned visual stimuli induce loss of MEF2 via NMDARs and caspases-9, -3/7 ► Knockdown of MEF2 is sufficient to induce a metaplastic shift in plasticity responses