Identification of Munc13-3 as a Candidate Gene for Critical-Period Neuroplasticity in Visual Cortex

Abstract

The first several months of life are a critical period for neuronal plasticity in the visual cortex during which anatomic and physiological development depends on visual experience. In cats, electrophysiologically assessed neuronal plasticity is minimal until approximately 3 weeks, peaks at 5 weeks, gradually declines to low levels at 20 weeks, and disappears at approximately 1 year of age (Daw, 1994). Rearing in darkness slows the entire time course of this critical period, such that at 5 weeks of age, normal cats are more plastic than dark-reared cats, whereas at 20 weeks, dark-reared cats are more plastic (Mower, 1991; Beaver et al., 2001). Thus, a stringent criterion is that genes that are important for plasticity in visual cortex will show differences in expression between normal rearing and dark rearing that are of opposite direction in young versus older animals. The present study reports the identification by differential display PCR of Munc13-3, a mammalian homolog of the Caenorhabditis elegans "uncoordinated" gene (unc-13), as a candidate gene for critical-period neuronal plasticity, the expression of which is regulated according to this criterion specifically in visual cortex and not in frontal cortex. Other members of the Munc13 family (Munc13-1 and Munc13-2) do not meet this criterion in visual cortex, indicating that Munc13-3 is the only family member that is regulated by age and dark rearing in the same manner as physiological plasticity during the visual cortical critical period.

Bidirectional regulation of Munc13–3 protein expression by age and dark rearing during the critical period in mouse visual cortex

“…Munc13-1 was expressed in all structures and more abundant in the cortex as compared to the cerebellum; Munc13-2 was expressed in the cortex as well, but was not detected in the cerebellum; Munc13-3 was expressed in all structures but was more abundant in the cerebellum compared to the cortex. These different regional patterns of expression of the Munc13 proteins are in agreement with the pattern of the mRNAs reported in the cat (Yang et al, 2002). Moreover, these expression patterns are in general agreement with the expression patterns of Munc13 proteins previously reported in the forebrain and hindbrain of the rat (Augustin et al, 1999a(Augustin et al, ,2001.…”

“…In a differential gene screen of normal and dark-reared cat visual cortex at the peak and nadir of the critical period, two different patterns of bidirectional regulation of gene expression were uncovered (Yang et al, , 2002(Yang et al, , 2006. One pattern, elevation in normal at the peak of the critical period and elevation in dark-reared at the nadir, is the pattern indicated by electrophysiological results (Mower, 1991;Beaver et al, 2001).…”

“…Differential display PCR screening of normal and dark-reared cat visual cortex at 5 and 20 weeks has identified Munc13-3 as a gene which shows such bidirectional regulation (Yang et al, 2002). Munc13-3 is a member of a family of proteins (including Munc13-1 and Munc13-2), all of which play a role in synaptic vesicle priming in glutamatergic and GABAergic synapses (Augustin et al, 1999b;Brose et al, 1998;Varoqueaux et al, 2002).…”

Structural Dynamics of Synapsesin VivoCorrelate with Functional Changes during Experience-Dependent Plasticity in Visual Cortex

“…In animals reared in darkness from birth, functional changes in visual cortical neurons include reduced spatial acuity, orientation and direction selectivity, along with reduced cortical responsiveness (Czepita et al, 1994; Fagiolini et al, 1994). This is accompanied by structural changes in dendritic spine morphology (Winkelmann et al, 1976; Wallace and Bear, 2004), as well as molecular changes that hint at both altered presynaptic (Yang et al, 2002) and postsynaptic (Cotrufo et al, 2003; Tropea et al, 2006) function, and changes in intracellular and extracellular signaling (Lander et al, 1997; Tropea et al, 2006). Exposure to light following dark-rearing reverses many of these effects, restoring molecular (Philpot et al, 2001; Tropea et al, 2001; Cotrufo et al, 2003), structural (Valverde, 1971; Wallace and Bear, 2004) and functional (Buisseret et al, 1982; Li et al, 2006) properties of cortical neurons.…”

Munc13-3 mutation prevents critical period neuronal plasticity in visual cortex.

“…Munc13-3 is part of the unc-13 gene family that is seen to be expressed throughout the brain, with munc13-3 mostly being observed caudally (Brose et aI., 1995;Augustin et aI., 1999b;Yang et at, 2002). All three isoforms ofthe munc 13 gene are found to be involved in the regulation of exocytosis of synaptic vesicles and thus involved in neurotransmitter release, particularly glutamate (Augustin et aI., 2001;Basu et al, 2007).…”