Contactin-associated protein-like 2 (Caspr2) is found at the nodes of Ranvier and has been associated with physiological properties of white matter conductivity. Genetic variation in CNTNAP2, the gene encoding Caspr2, has been linked to several neurodevelopmental conditions, yet pathophysiological effects of CNTNAP2 mutations on axonal physiology and brain myelination are unknown. Here, we have investigated mouse mutants for Cntnap2 and found profound deficiencies in the clustering of Kv1-family potassium channels in the juxtaparanodes of brain myelinated axons. These deficits are associated with a change in the waveform of axonal action potentials and increases in postsynaptic excitatory responses. We also observed that the normal process of myelination is delayed in Cntnap2 mutant mice. This later phenotype is a likely modulator of the developmental expressivity of the stereotyped motor behaviors that characterize Cntnap2 mutant mice. Altogether, our results reveal a mechanism linked to white matter conductivity through which mutation of CNTNAP2 may affect neurodevelopmental outcomes.

Neural circuit assembly relies on the precise synchronization of developmental processes, such as cell migration and axon targeting, but the cell-autonomous mechanisms coordinating these events remain largely unknown. Here we found that different classes of interneurons use distinct routes of migration to reach the embryonic cerebral cortex. Somatostatin-expressing interneurons that migrate through the marginal zone develop into Martinotti cells, one of the most distinctive classes of cortical interneurons. For these cells, migration through the marginal zone is linked to the development of their characteristic layer 1 axonal arborization. Altering the normal migratory route of Martinotti cells by conditional deletion of Mafb-a gene that is preferentially expressed by these cells-cell-autonomously disrupts axonal development and impairs the function of these cells in vivo. Our results suggest that migration and axon targeting programs are coupled to optimize the assembly of inhibitory circuits in the cerebral cortex.

Pregnant women who are obese or whose gestational weight gain is above recommended limits are at increased risk of obstetric complications, 1 but there may also be longer term consequences for the health of the child.2 A high maternal prepregnancy body mass index and excessive gestational weight gain have been frequently independently associated with a heightened risk of offspring metabolic dysfunction and obesity 3 and there is increasing evidence to suggest that cardiovascular function may also be compromised. 4 Studies of maternal calorie-rich diets and obesity in rodents, sheep, and nonhuman primates have provided unequivocal evidence for persistent and adverse influences on the offspring. 5 We and others have repeatedly observed cardiovascular dysfunction secondary to maternal obesity in animal models. [6][7][8] Previously, we observed that juvenile offspring of obese rats have aberrant autonomic control of blood pressure (BP) resulting in hypertension, which occurs before the development of increased adiposity and persists into adulthood, 7 and that these animals demonstrate hyperphagia and leptin resistance associated with a functional, structural, and cell-signaling deficit in leptin-sensitive processes in the arcuate nucleus and paraventricular nucleus of the hypothalamus. 9 The cardiovascular response to exogenous leptin, which is mediated through hypothalamic sympathetic efferent activity, 10,11 was, conversely, enhanced. 7 This differential response to leptin, sometimes termed selective leptin resistance, had been observed in rodents, but previously only in association with chronic obesity. 12 We also reported that the offspring of obese dams (OffOb) exhibit an exaggerated and prolonged physiological postnatal serum leptin surge, 9 known to play a critical role in the development of the normal rodent hypothalamus. 13 We hypothesized that neonatal exposure to supranormal leptin concentrations during this important window of hypothalamic plasticity may play a causal role in offspring cardiovascular Abstract-The prevalence of obesity among pregnant women is increasing. Evidence from human cohort studies and experimental animals suggests that offspring cardiovascular and metabolic function is compromised through early life exposure to maternal obesity. Previously, we reported that juvenile offspring of obese rats develop sympathetically mediated hypertension associated with neonatal hyperleptinemia. We have now addressed the hypothesis that neonatal exposure to raised leptin in the immediate postnatal period plays a causal role. Pups from lean Sprague-Dawley rats were treated either with leptin (3 mg/kg IP) or with saline twice daily from postnatal day 9 to 15 to mimic the exaggerated postnatal leptin surge observed in offspring of obese dams. Cardiovascular function was assessed by radiotelemetry at 30 days, and 2 and 12 months. In juvenile (30 days) leptin-treated rats, hearts were heavier and night-time (active period) systolic blood pressure was raised (mm Hg; mean±SEM: male leptin-treated, 132±1 v...

Melanocortin-4 receptor (Mc4r)-expressing neurons in the autonomic nervous system, particularly in the paraventricular nucleus of the hypothalamus (PVH), play an essential role in blood pressure (BP) control. mice are severely obese but lack obesity-related hypertension; they also show a reduced pressor response to salt loading. We have previously reported that lean juvenile offspring born to diet-induced obese rats (OffOb) exhibit sympathetic-mediated hypertension, and we proposed a role for postnatally raised leptin in its etiology. Here, we test the hypothesis that neonatal hyperleptinemia due to maternal obesity induces persistent changes in the central melanocortin system, thereby contributing to offspring hypertension. Working on the OffOb paradigm in both sexes and using transgenic technology to restore Mc4r in the PVH of Mc4rKO (Mc4rPVH) mice, we have now shown that these mice develop higher BP than Mc4rKO or WT mice. We have also found that experimental hyperleptinemia induced in the neonatal period in Mc4rPVH and WT mice, but not in the Mc4rKO mice, leads to heightened BP and severe renal dysfunction. Thus, Mc4r in the PVH appears to be required for earlylife programming of hypertension arising from either maternal obesity or neonatal hyperleptinemia. Early-life exposure of the PVH to maternal obesity through postnatal elevation of leptin may have long-term consequences for cardiovascular health.melanocortin-4 receptors | developmental programming | maternal obesity | hypertension | sympathetic nerve activity T he main focus of research into the central melanocortin system has been on melanocortin-4 receptor(s) (Mc4r) and their relation to energy homeostasis, with relatively few studies addressing the role of Mc4r in cardiovascular control (1, 2). However, it is clear that this system plays an important role in the control of blood pressure (BP) (3, 4). In humans with loss-of-function Mc4r mutation, there is severe obesity but no obesity-related hypertension (5). Mc4r-deficient (Mc4rKO) mice exhibit hyperphagia and marked obesity and, similarly, no obesity-related hypertension (3). Mc4r deletion also reduces the pressor response to salt loading, as well as preventing inflammatory and renal damage associated with obesity (6). Pharmacological inhibition of Mc4r in adult rats reduces the obesity-related hypertension and renal sympathetic nerve activity (RSNA) associated with hyperleptinemia (7,8). Moreover, the highest expression of hypothalamic Mc4r mRNA is found in the paraventricular nucleus of the hypothalamus (PVH), which integrates and responds to a variety of neural and humoral signals regulating RSNA (9-12). It has been shown that leptin stimulates the tonic firing rate of Mc4r PVH neurons in rats, resulting in heightened arterial pressure, a finding that is consistent with causal links between obesity and adult hypertension (13).The increased prevalence of hypertension among children and young adults has been attributed to sympathetic hyperactivity (14). Although genetic and lifestyle factors un...