DEFINE · DEciphering mechanisms of presynaptic reFINEment

DEciphering mechanisms of presynaptic reFINEment

Despite extensive research efforts much remains unknown about of how mature brain circuits form and how this is coordinated with sensory experience. Initial wiring is refined during postnatal critical periods. Revealing the roles of genes and timings of circuit refinement is critical to understand how healthy brains form and how disorders such as autism and depression occur which are a major health burden. A well-known family of synaptic receptors that regulate neuronal connections are NMDA receptors (NMDARs). Classical NMDARs containing GluN1 and GluN2 subunits promote synapse maturation through their biophysical and signalling properties. An alternative subunit called GluN3A confers different properties to receptors. The expression of GluN3A peaks during postnatal stages coinciding with critical refinement periods and absence of GluN3A causes increased numbers of dendritic spines. Existing work has focused on postsynaptic effects of GluN3A. The limited work on presynaptic roles have focused on functional readouts rather than morphology and targeting. The DEFINE project aimed to address this by analysis of a major cortical circuit, the interhemispheric callosal axons. This circuit is refined during postnatal ages when GluN3A is expressed there. The primary objective of the project were to assess how global loss of GluN3A affects callosal axonal arborisation and targeting as a readout of presynaptic connectivity. A key objective was to narrow down the cellular location of function within the callosal circuit by genetic loss of Grin3a function in particular cell populations. An ambitious goal was to also test for a role of neuronal activity and sensory experience in mediating any GluN3A axonal effects. A parallel objective was to identify and dissect the molecular mediators of GluN3A´s role in affecting axon refinement and targeting. A further objective was to study potential functional impacts of the altered callosal circuit connectivity by recording neuronal activity in vivo. Project conclusions - GluN3A impacts the targeting and refinement of L2/3 callosal axons to ensure appropriate arborization patterns and regional targeting during later postnatal ages. - These effects do not arise from GluN3A expression in presynaptic cells or SST inhibitory neurons but likely from postsynaptic changes indicated by altered dendritic morphology of L2/3 neurons. - Extracellular activity recordings found changes in Grin3a KOs consistent with altered local and interhemispheric connectivity that although do not directly correlate to the axonal changes are key progress to understanding the functional effects of GluN3A on the brain. - Confirmed changes in protein expression of KIRREL2, CRMP4 and KCNA1 provide exciting candidates that may mediate GluN3A effects on the callosal axon circuit.

Текст от CORDIS, на английски · Данни: CORDIS, © Европейски съюз