Abstract
The dynamic regulation of the actin cytoskeleton plays a key role in controlling the structure and function of synapses. It is vital for activity-dependent modulation of synaptic transmission and long-term changes in synaptic morphology associated with memory consolidation. Several regulators of actin dynamics at the synapse have been identified, of which a salient one is the postsynaptic actin stabilising protein Drebrin (DBN). It has been suggested that DBN modulates neurotransmission and changes in dendritic spine morphology associated with synaptic plasticity. Given that a decrease in DBN levels is correlated with cognitive deficits associated with ageing and dementia, it was hypothesised that DBN protein abundance instructs the integrity and function of synapses. We created a novel DBN deficient mouse line. Analysis of gross brain and neuronal morphology revealed no phenotype in the absence of DBN. Electrophysiological recordings in acute hippocampal slices and primary hippocampal neuronal cultures showed that basal synaptic transmission, and both long-term and homeostatic synaptic plasticity were unchanged, suggesting that loss of DBN is not sufficient in inducing synapse dysfunction. We propose that the overall lack of changes in synaptic function and plasticity in DBN deficient mice may indicate robust compensatory mechanisms that safeguard cytoskeleton dynamics at the synapse.
Highlights
Pathological changes associated with spine morphology and structural plasticity deficits occur in a variety of neurological disorders accompanied by cognitive decline such as seen in Alzheimer’s disease[16]
DBN KO mice were obtained by crossing homozygote pre-conditional mice (Dbn1loxp/loxp) with a Cre/loxP-deleter strain, which induced the expected excision of exon 1–6 between loxP sites (Fig. 1a,b; Fig. S1a)
Comparing the size of the afferent fibre volley (FV) as a measure for the excitation of presynaptic fibers, with the slope of the fEPSP representing the postsynaptic responsiveness, we found no significant differences between the two groups in their input–output relationship. (Fig. 2a,b; wild type (WT) N = 3, n = 19; KO N = 3, n = 21; P > 0.05; Fig. S1a,b; WT N = 3, n = 18; KO N = 3, n = 14; P > 0.05, two-way ANOVA, Bonferroni post-hoc test), which is in agreement with previous studies using acute slice preparations of DBN deficient mouse models[30,31]
Summary
It has been suggested that LTP inducing stimuli induce a transient exodus and subsequently, re-entry of DBN into dendritic spines[4,26] resulting in a net-increase of DBN in potentiated spines[27]. Two mouse models of DBN deficiency have been previously published, one being deficient for the isoform conversion of DBN A from DBN E29 and a DBN KO mouse generated by excision of DBN exons 4–730. Both models show reduced hippocampal LTP and altered spine morphology in CA1 hippocampal neurons[30,31]. Our data argue against a prominent role of DBN in mediating changes in synaptic strength at hippocampal excitatory synapses, at least in the healthy young adult brain
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