Ablation of the presynaptic organizer Bassoon in excitatory neurons retards dentate gyrus maturation and enhances learning performance

Abstract

Bassoon is a large scaffolding protein of the presynaptic active zone involved in the development of presynaptic terminals and in the regulation of neurotransmitter release at both excitatory and inhibitory brain synapses. Mice with constitutive ablation of the Bassoon (Bsn) gene display impaired presynaptic function, show sensory deficits and develop severe seizures. To specifically study the role of Bassoon at excitatory forebrain synapses and its relevance for control of behavior, we generated conditional knockout (Bsn cKO) mice by gene ablation through an Emx1 promoter-driven Cre recombinase. In these animals, we confirm selective loss of Bassoon from glutamatergic neurons of the forebrain. Behavioral assessment revealed that, in comparison to wild-type littermates, Bsn cKO mice display selectively enhanced contextual fear memory and increased novelty preference in a spatial discrimination/pattern separation task. These changes are accompanied by an augmentation of baseline synaptic transmission at medial perforant path to dentate gyrus (DG) synapses, as indicated by increased ratios of field excitatory postsynaptic potential slope to fiber volley amplitude. At the structural level, an increased complexity of apical dendrites of DG granule cells can be detected in Bsn cKO mice. In addition, alterations in the expression of cellular maturation markers and a lack of age-dependent decrease in excitability between juvenile and adult Bsn cKO mice are observed. Our data suggest that expression of Bassoon in excitatory forebrain neurons is required for the normal maturation of the DG and important for spatial and contextual memory.Electronic supplementary materialThe online version of this article (10.1007/s00429-018-1692-3) contains supplementary material, which is available to authorized users.

Neuronal BIN1 Regulates Presynaptic Neurotransmitter Release and Memory Consolidation

“…The levels of GluA1 and pCamKII (Thr286) were also reduced, but the decrease in GluA1 was statistically significant only in Emx mice, and the reduction of pCaMKII was significant only in Syn mice ( Figure 1F; Table S2). Synaptoporin and Munc13-1 are involved in presynaptic vesicle regulation and SNARE complex association (He et al, 2017;Li et al, 2017;Singec et al, 2002), and Bassoon is an organizer of the docking area at the presynaptic site (Annamneedi et al, 2018;Gundelfinger et al, 2016). These results suggested that the loss of BIN1 leads to a potential defect in synaptic density and the organization of synaptic proteins, including SNARE proteins at the presynaptic sites.…”

Persistent increase in ventral hippocampal long‐term potentiation by juvenile stress: A role for astrocytic glutamine synthetase

“…The presynaptic response, reflected by the FV amplitude, was not significantly altered by exposure to juvenile stress, adult stress, or the combination of both. Based on the ratio of postsynaptic fEPSP slope and presynaptic fiber volley responses upon stimulation, it is possible to assess the efficacy of synaptic transmission (Annamneedi et al, 2018;Chen et al, 2000;Nguyen et al, 2000;Patterson et al, 1996), which was reduced after juvenile stress in our experiments.…”

“…The fiber volley (FV) amplitude was measured by calculating the peak-to-peak amplitude of the descending phase of the FV. To analyze the efficacy of synaptic transmission, the slope of the postsynaptic fEPSP was divided by the amplitude of the corresponding presynaptic FV as previously published by us and others ( Figure 1b; Annamneedi et al, 2018;Chen, Kagan, Hirakura, & Xie, 2000;Nguyen, Abel, Kandel, & Bourtchouladze, 2000;Patterson et al, 1996).…”

Thirteen independent genetic loci associated with preserved processing speed in a study of cognitive resilience in 330,097 individuals in the UK Biobank

“…Many of these 33 genes have been connected with cognitive performance, neurodegenerative disorders or aging and represent potential therapeutic targets: STAU1 (chr 20) and SEMA3F (chr 3) are predicted to control cognitive decline in aging through formation of neural circuits and synaptic transmission [22]. BNS (chr 3) codes for bassoon presynaptic cytomatrix protein which is implicated in the regulation of neurotransmitters at inhibitory and excitatory synapses [23]. IP6K1 (chr 3) codes for inositol pyrophosphate biosynthesis, and mouse studies have shown its involvement in short term memory by altering presynaptic vesicle release and short-term facilitation of glutamatergic synapses in the hippocampus [24].…”