New functions of Semaphorin 3E and its receptor PlexinD1 during developing and adult hippocampal formation

The development and maturation of cortical circuits relies on the coordinated actions of long and short range axonal guidance cues. In this regard, the class 3 semaphorins and their receptors have been seen to be involved in the development and maturation of the hippocampal connections. However, although the role of most of their family members have been described, very few data about the participation of Semaphorin 3E (Sema3E) and its receptor PlexinD1 during the development and maturation of the entorhino-hippocampal (EH) connection are available. In the present study, we focused on determining their roles both during development and in adulthood. We determined a relevant role for Sema3E/PlexinD1 in the layer-specific development of the EH connection. Indeed, mice lacking Sema3E/PlexinD1 signalling showed aberrant layering of entorhinal axons in the hippocampus during embryonic and perinatal stages. In addition, absence of Sema3E/PlexinD1 signalling results in further changes in postnatal and adult hippocampal formation, such as numerous misrouted ectopic mossy fibers. More relevantly, we describe how subgranular cells express PlexinD1 and how the absence of Sema3E induces a dysregulation of the proliferation of dentate gyrus progenitors leading to the presence of ectopic cells in the molecular layer. Lastly, Sema3E mutant mice displayed increased network excitability both in the dentate gyrus and the hippocampus proper

Dynamics of brain states and cortical excitability in paroxysmal neurological conditions

Epilepsy and migraine are neurological conditions that are characterised by periods of disruption of normal neuronal functioning. Aside from this paroxysmal feature, both conditions share genetic mutations and altered cortical excitability. People with epilepsy appear to be diagnosed with migraine more often than people without epilepsy and, likewise, people with migraine seem to be diagnosed with epilepsy more often than people without migraine. Changes in cortical excitability may help explain the pathophysiological link between both conditions, and could be a biomarker to monitor disease activity. In this thesis, the association between migraine and epilepsy and their relation to cortical excitability is further explored. A meta-analysis of previous population based studies provides epidemiological evidence for the co-occurrence of migraine and epilepsy. The combination of computer modelling with human electroencephalographic recordings offers insight into multi-stability of brain states in epilepsy. Results described in this thesis show that Transcranial Magnetic Stimulation can be used to measure cortical excitability, but that its use as a biomarker of disease activity in epilepsy is limited due to large interindividual variability. By combining Transcranial Magnetic Stimulation with electroencephalography, two novel variables that may contribute to cortical excitability are investigated: phase clustering, which possibly reflecting functional neuronal connectivity, and the non-linear residual of a stimulus-response curve, which may reflect brain state multi-stability. The results presented in this thesis suggest that the higher propensity to global synchronisation is not shared between epilepsy and migraine. These new variables have potential value to differentiate people with epilepsy, but not people with migraine, from normal controls