Abstract
A presynaptic active zone organizer protein Bassoon orchestrates numerous important functions at the presynaptic active zone. We previously showed that the absence of Bassoon exclusively in forebrain glutamatergic presynapses (BsnEmx1cKO) in mice leads to developmental disturbances in dentate gyrus (DG) affecting synaptic excitability, morphology, neurogenesis and related behaviour during adulthood. Here, we demonstrate that hyperexcitability of the medial perforant path-to-DG (MPP-DG) pathway in BsnEmx1cKO mice emerges during adolescence and is sustained during adulthood. We further provide evidence for a potential involvement of tropomyosin-related kinase B (TrkB), the high-affinity receptor for brain-derived neurotrophic factor (BDNF), mediated signalling. We detect elevated TrkB protein levels in the dorsal DG of adult mice (~3–5 months-old) but not in adolescent (~4–5 weeks-old) mice. Electrophysiological analysis reveals increased field-excitatory-postsynaptic-potentials (fEPSPs) in the DG of the adult, but not in adolescent BsnEmx1cKO mice. In line with an increased TrkB expression during adulthood in BsnEmx1cKO, blockade of TrkB normalizes the increased synaptic excitability in the DG during adulthood, while no such effect was observed in adolescence. Accordingly, neurogenesis, which has previously been found to be increased in adult BsnEmx1cKO mice, was unaffected at adolescent age. Our results suggest that Bassoon plays a crucial role in the TrkB-dependent postnatal maturation of the hippocampus.
Highlights
Transition from adolescence into adulthood requires a substantial remodelling of limbic and cortical circuits
Our results suggest that Bsn deficiency in forebrain excitatory neurons leads to aberrant maturation of hippocampal circuits possibly via an abnormal tropomyosin-related kinase B (TrkB)-mediated signalling during transition from adolescence to adulthood
In the current study, we aimed at gaining insights into the potential signalling mech
Summary
Transition from adolescence into adulthood requires a substantial remodelling of limbic and cortical circuits (e.g., hippocampus). Comparison of half maximal fEPSP slopes revealed only a general genotype difference (Figure 2F, F(1, 45) = 5.339, p = 0.025) without any treatment effect (Figure 2F, F(1, 45) = 0.301, p = 0.586) and treatment x genotype interaction (Figure 2F, F(1, 45) = 0.438, p = 0.511) These data indicate that synaptic hyperexcitability observed at the DG-MPP is a result of elevated TrkB levels and can be rescued by the blockade of TrkB-mediated signalling whereas the impact of this intervention is minimal in reducing hyperexcitability at the SC-CA1 synapse of BsnEmx1cKO mice. Half maximal fEPSP slope values (Figure 4F) were not affected (genotype: F(1, 41) = 0.107, p = 0.745; treatment: F(1, 41) = 1.321, p = 0.257) Together, these data suggest that hippocampal hyperexcitability and its interaction with TrkB-mediated signalling is only evident in adult BsnEmx1cKO mice as no changes were detected at this young age.
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