Brain Volumes in Mice are Smaller at Birth After Term or Preterm Cesarean Section Delivery.

The rate of cesarean section (CS) delivery has steadily increased over the past decades despite epidemiological studies reporting higher risks of neonatal morbidity and neurodevelopmental disorders. Yet, little is known about the immediate impact of CS birth on the brain, hence the need of experimental studies to evaluate brain parameters following this mode of delivery. Using the solvent clearing method iDISCO and 3D imaging technique, we report that on the day of birth, whole-brain, hippocampus, and striatum volumes are reduced in CS-delivered as compared to vaginally-born mice, with a stronger effect observed in preterm CS pups. These results stress the impact of CS delivery, at term or preterm, during parturition and at birth. In contrast, cellular activity and apoptosis are reduced in mice born by CS preterm but not term, suggesting that these early-life processes are only impacted by the combination of preterm birth and CS delivery.

Pro-Brain-Derived Neurotrophic Factor (proBDNF)-Mediated p75NTR Activation Promotes Depolarizing Actions of GABA and Increases Susceptibility to Epileptic Seizures.

The brain-derived neurotrophic factor (BDNF) is synthesized as a precursor, namely proBDNF, which can be processed into mature BDNF (mBDNF). Evidences suggest that proBDNF signaling through p75NTR may account for the emergence of neurological disorders. These findings support the view that the relative availability of mBDNF and proBDNF forms is an important mechanism underlying brain circuit formation and cognitive functions. Here we describe novel insights into the proBDNF/p75NTR mechanisms and function in vivo in modulating neuronal circuit and synaptic plasticity during the first postnatal weeks in rats. Our results showed that increased proBDNF/p75NTR signaling during development maintains a depolarizing γ-aminobutyric acid (GABA) response in a KCC2-dependent manner in mature neuronal cells. This resulted in altered excitation/inhibition balance and enhanced neuronal network activity. The enhanced proBDNF/p75NTR signaling ultimately led to increased seizure susceptibility that was abolished by in vivo injection of function blocking p75NTR antibody. Altogether, our study shed new light on how proBDNF/p75NTR signaling can orchestrate the GABA excitatory/inhibitory developmental sequence leading to depolarizing and excitatory actions of GABA in adulthood and subsequent epileptic disorders.

Pro-brain-derived neurotrophic factor inhibits GABAergic neurotransmission by activating endocytosis and repression of GABAA receptors.

GABA is the canonical inhibitory neurotransmitter in the CNS. This inhibitory action is largely mediated by GABA type A receptors (GABAARs). Among the many factors controlling GABAergic transmission, brain-derived neurotrophic factor (BDNF) appears to play a major role in regulating synaptic inhibition. Recent findings have demonstrated that BDNF can be released as a precursor (proBDNF). Although the role of mature BDNF on GABAergic synaptogenesis and maintenance has been well studied, an important question still unanswered is whether secreted proBDNF might affect GABAergic neurotransmission. Here, we have used 14 d in vitro primary culture of hippocampal neurons and ex vivo preparations from rats to study the function of proBDNF in regulation of GABAAR trafficking and activity. We demonstrate that proBDNF impairs GABAergic transmission by the activation of two distinct pathways: (1) a RhoA-Rock-PTEN pathway that decreases the phosphorylation levels of GABAAR, thus affecting receptor function and triggering endocytosis and degradation of internalized receptors, and (2) a JAK-STAT-ICER pathway leading to the repression of GABAARs synthesis. These effects lead to the diminution of GABAergic synapses and are correlated with a decrease in GABAergic synaptic currents. These results revealed new functions for proBDNF-p75 neurotrophin receptor signaling pathway in the control of the efficacy of GABAergic synaptic activity by regulating the trafficking and synthesis of GABAARs at inhibitory synapses.