Sonic Hedgehog Signaling Agonist (SAG) Triggers BDNF Secretion and Promotes the Maturation of GABAergic Networks in the Postnatal Rat Hippocampus.

Sonic hedgehog (Shh) signaling plays critical roles during early central nervous system development, such as neural cell proliferation, patterning of the neural tube and neuronal differentiation. While Shh signaling is still present in the postnatal brain, the roles it may play are, however, largely unknown. In particular, Shh signaling components are found at the synaptic junction in the maturing hippocampus during the first two postnatal weeks. This period is characterized by the presence of ongoing spontaneous synaptic activity at the cellular and network levels thought to play important roles in the onset of neuronal circuit formation and synaptic plasticity. Here, we demonstrate that non-canonical Shh signaling increases the frequency of the synchronized electrical activity called Giant Depolarizing Potentials (GDP) and enhances spontaneous GABA post-synaptic currents in the rodent hippocampus during the early postnatal period. This effect is mediated specifically through the Shh co-receptor Smoothened via intracellular Ca2+ signal and the activation of the BDNF-TrkB signaling pathway. Given the importance of these spontaneous events on neuronal network maturation and refinement, this study opens new perspectives for Shh signaling on the control of early stages of postnatal brain maturation and physiology.

From cerebral palsy to developmental coordination disorder: Development of preclinical rat models corresponding to recent epidemiological changes.

Cerebral palsy (CP) is a complex syndrome of various sensory, motor and cognitive deficits. Its prevalence has recently decreased in some developed countries and its symptoms have also shifted since the 1960s. From the 1990s, CP has been associated with prematurity, but recent epidemiologic studies show reduced or absent brain damage, which recapitulates developmental coordination disorder (DCD). In previous studies, we developed a rat model based on mild intrauterine hypoperfusion (MIUH) that recapitulated the diversity of symptoms observed in preterm survivors. Briefly, MIUH led to early inflammatory processes, diffuse brain damage, minor locomotor deficits, musculoskeletal pathologies, neuroanatomical and functional disorganization of the primary somatosensory (S1) cortex but not in the motor cortex (M1), delayed sensorimotor reflexes, spontaneous hyperactivity, deficits in sensory information processing, and memory and learning impairments in adult rats. Adult MIUH rats also exhibited changes in muscle contractile properties and phenotype, enduring hyperreflexia and spasticity, as well as hyperexcitability in the sensorimotor cortex. We recently developed a rat model of DCD based on postnatal sensorimotor restriction (SMR) without brain damage. Briefly, SMR led to digitigrade locomotion (i.e., "toe walking") related to ankle-knee overextension, degraded musculoskeletal tissues (e.g., gastrocnemius atrophy), and lumbar hyperreflexia. The postnatal SMR then led to secondary degradation of the hind-limb maps in S1 and M1 cortices, altered cortical response properties and cortical hyperexcitability, but no brain damage. Thus, our 2 rat models appear to recapitulate the diversity of symptoms ranging from CP to DCD and contribute to understanding the emergence and mechanisms underlying the corresponding neurodevelopmental disorders. These preclinical models seem promising for testing strategies of rehabilitation based on both physical and cognitive training to promote adaptive brain plasticity and to improve physical body conditions.