Structural and functional differences in the barrel cortex of Mecp2 null mice

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Rett syndrome (RTT) is a neurodevelopmental disorder caused by mutations in the MECP2 gene on the X chromosome located at Xq28 (Amir et al., 1999). MECP2 acts as a transcription repressor or activator of many genes throughout the genome and its loss of function or overexpression leads to cognitive and behavioral deficits observed in childhood development (Calfa, Percy, & Pozzo‐Miller, 2011; Kaufmann, Johnston, & Blue, 2005; Na, Nelson, Kavalali, & Monteggia, 2013). In the mouse brain, Mecp2 protein and mRNA expression is widespread, and conspicuous in the thalamus and neocortex (Dragich, Kim, Arnold, & Schanen, 2007; Jung et al., 2003; Kishi & Macklis, 2004). Several studies have examined aspects of dendritic differentiation, spine genesis, and electrophysiological properties of Mecp2 mutant neurons in different regions of the mouse brain, such as the hippocampus and the prefrontal cortex. However, no systematic study has been done in the developing somatosensory (barrel) cortex in Mecp2 constitutive or region‐specific mutants to investigate how Mecp2 deletion affects the thalamocortical synaptic circuitry of the somatosensory system.
Mecp2 is X‐linked and mutant homozygous female mice do not survive; males carrying the mutation (−/y) survive and are considered Mecp2‐null. Mecp2 null mice exhibit several characteristics of RTT at 3–8 weeks of age, while heterozygous female mice exhibit some of the characteristics of RTT after 6 months. Several research groups have generated Mecp2 mutant mouse lines. The initial constitutive Mecp2 deletion resulted in embryonic lethality (Tate, Skarnes, & Bird, 1996). Adrian Bird's laboratory circumvented embryonic lethality by conditional gene deletion approach. The resultant mouse line is known as the Bird model (Guy, Hendrich, Holmes, Martin, & Bird, 2001). Breeding Mecp2 heterozygous (Mecp2+/−) females with C57BL/6 males yield heterozygous females and hemizygous (Mecp2−/y) males; hemizygous males do not breed.
In many neurodevelopmental disorders, such as RTT, sensory processing deficits are common. A conspicuous behavioral stereotypy in children with RTT is hand to mouth kneading movements, which has both tactile sensory and motor components. In the human primary somatosensory cortex, proportionately largest areas are devoted to the hands and mouth. Likewise, in the mouse primary somatosensory cortex, a very large area is devoted to the representation of the facial whiskers. In fact, each whisker has a distinct, corresponding neural module known as a “barrel” because of the arrangement of layer IV neurons in a cylindrical array, with its center (hollow) filled by the discrete terminal arbors of thalamocortical axon (TCA) arbors corresponding to single whiskers (Agmon, Yang, Jones, & O'Dowd, 1995; Lee, Iwasato, Itohara, & Erzurumlu, 2005; Rebsam, Seif, & Gaspar, 2002; Senft & Woolsey, 1991; Woolsey & Van der Loos, 1970). Thus, the whisker‐barrel pathway of mice provides a unique model to study sensory processing defects in mutant mouse models of neurodevelopmental disorders.
In this study, we investigated peripherally evoked sensory activity in the barrel cortex of male Mecp2 null mice and present analysis of the morphological differentiation of TCA terminals and dendrites of the barrel cells that receive peripherally evoked activity through them.
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