The complex role of protocadherin-19 in brain function:a focus on the oxytocin system

Mutations in the protocadherin-19(PCDH19)gene(Xq22.1)cause the X-linked syndrome known as developmental and epileptic encephalopathy 9(DEE9,OMIM#300088)(Dibbens et al.,2008).DEE9 is characterized by early-onset clustering epilepsy associated with intellectual disability ranging from mild to profound,autism spectrum disorder,and other neuropsychiatric features including schizophrenia,anxiety,attentiondeficit/hyperactivity,and obsessive or aggressive behaviors.While seizures may become less frequent in adolescence,psychiatric comorbidities persist and often worsen with age(Dibbens et al.,2008;Kolc et al.,2020).

Neural plasticity and adult neurogenesis: the deep biology perspective

The recognition that neurogenesis does not stop with adolescence has spun off research towards the reduction of brain disorders by enhancing brain regeneration. Adult neurogenesis is one of the tougher problems of developmental biology as it requires the generation of complex intracellular and pericellular anatomies, amidst the danger of neuroinflammation. We here review how a multitude of regulatory pathways optimized for early neurogenesis has to be revamped into a new choreography of time dependencies. Distinct pathways need to be regulated, ranging from neural growth factor induced differentiation to mitochondrial bioenergetics, reactive oxygen metabolism, and apoptosis. Requiring much Gibbs energy consumption, brain depends on aerobic energy metabolism, hence on mitochondrial activity. Mitochondrial fission and fusion, movement and perhaps even mitoptosis, thereby come into play. All these network processes are interlinked and involve a plethora of molecules. We recommend a deep thinking approach to adult neurobiology.

PCDH19 interplay with GABA(A)receptors:a window to DEE9 pathogenetic mechanisms

Developmental and epileptic encephalopathy 9(DEE9):The gene PCDH19(Xq22.1),which encodes the calcium-dependent cell adhesion protein protocadherin-19(PCDH19),is nowadays considered as one of the most important genes in monogenic epilepsy(Depienne and LeGuern,2012).Mutations in PCDH19 are responsible for DEE9(OMIM#300088),a severe neurodevelopmental disorder characterized by early-onset clustering epilepsy,various degrees of cognitive impairment and neuro psychiatric comorbidities,like autism spectrum disorder(ASD)and behavioural problems.DEE9 patients start suffering from seizures around the age of 10 months until adolescence,when seizures tend to reduce or even disappear,while the psychiatric symptoms persist(Depienne and LeGuern,2012;Kolc et al.,2018).