Abstracts

Rationale: The broad association of epilepsy, autism, and related neurological disorders with dysfunctional bone metabolism [1] suggests a potential neural link between the cerebral cortex and bone that may underlie these deficits. In NS-Pten mice (neuronal subset-specific; Gfap-Cre;Pten^loxp/loxp), Phosphatase and tensin homolog (PTEN) deletion induces an overactive PI3K-Akt-mTOR pathway, resulting in macrocephaly, hypertrophic cortical neurons, and epileptiform activity with persistent seizures [2]. In this study, we present evidence that brain-specific knockout of the PTEN gene induces abnormal bone metabolism in growing mice. Methods: We used MicroCT analysis to measure trabecular bone volume and cortical area in the proximal tibia and mid-diaphysis bones of NS-PTEN wildtype and knockout mice at 8 weeks of age. We also measured locomotion in the open-field arena and motor learning in the accelerating rotarod test in mice 6 weeks of age. Results: 6wk NS-Pten mice exhibited forelimb clonus, spontaneous seizures, and hyperactivity in open field testing (p<0.001), as observed in previous studies [2,3]. NS-Pten mice also exhibited impaired motor learning, as indicated by decreased rotarod test performance (p<0.001). MicroCT analysis in 8wk NS-Pten mice revealed increased total volume in the proximal tibia (p<0.001) and mid-diaphysis (p<0.001), respectively, while TMD was lower in both locations (p<0.001). Effects of PTEN deletion were localized and compartment specific, as evidenced by the lower trabecular bone volume in the proximal tibia (p<0.05) but higher cortical area (but normal cortical thickness) in the mid-diaphysis (p<0.05). Conclusions: NS-Pten mice were recently shown to exhibit decreased hippocampal levels of the Kv4.2 potassium channel [3], which is associated with increased neuron excitability and seizure susceptibility [4]. MicroCT analysis of Kv4.2 knockout mice revealed no significant bone phenotype, suggesting that decreased Kv4.2 is not sufficient to alter skeletal activity. Collectively, these studies identify diverse morphological and densitometric bone alterations in mice with brain-specific PTEN deletion that is not attributable to decreased physical activity (an etiological factor broadly ascribed to account for low bone mass in epilepsy patients). Given the association of neuron-subset-specific Pten deletion with aberrant cortical brain activity, as well as the known influence of autonomic and sensory nerves on bone cell function, these studies provide an essential first step toward understanding the role of the cerebral cortex in the central regulation of bone metabolism. References: 1. Samaniego EA et al., 2007, Semin Pediatr Neurol 14:196-200; 2. Ljungberg MC et al., 2009, Dis Model Mech 7-8:389-398; 3. Lugo JN et al., 2014, Front Mol Neurosci, In Press; 4. Lugo JN et al., 2012, Learn Mem, 19:182-189