Abstract
Proper synaptic function depends on a finely-tuned balance between events such as protein synthesis and structural organization. In particular, the functional loss of just one synaptic-related protein can have a profound impact on overall neuronal network function. To this end, we used a mutant mouse model harboring a mutated form of the presynaptic scaffolding protein Bassoon (Bsn), which is phenotypically characterized by: (i) spontaneous generalized epileptic seizure activity, representing a chronically-imbalanced neuronal network; and (ii) a dramatic increase in hippocampal brain-derived neurotrophic factor (BDNF) protein concentration, a key player in synaptic plasticity. Detailed morphological and neurochemical analyses revealed that the increased BDNF levels are associated with: (i) modified neuropeptide distribution; (ii) perturbed expression of selected markers of synaptic activation or plasticity; (iii) subtle changes to microglial structure; and (iv) morphological alterations to the mossy fiber (MF) synapse. These findings emphasize the important contribution of Bassoon protein to normal hippocampal function, and further characterize the Bsn-mutant as a useful model for studying the effects of chronic changes to network activity.
Highlights
Proper hippocampal function depends on a finely-tuned balance between excitation and inhibition within the neuronal network, where any changes to this setting can have secondary effects on events such as protein synthesis and structural organization
Based on the observation that Bsn-mutants display a dramatic increase in hippocampal brain-derived neurotrophic factor (BDNF) protein concentration (Heyden et al, 2011), in the mossy fiber (MF) projection pathway (Dieni et al, 2012), it was of interest to investigate whether the immunohistochemical expression of two other small neuropeptides that are normally localized to MFs and known to modulate certain aspects of neuronal excitability was affected in the Bsn-mutant
Image overlay revealed a higher degree of overlap in comparison to WT sections between methionine form of enkephalin (Met-enk)-positive (+) and BDNF+ puncta in SL (Figure 1F), which at higher resolution was shown to correspond to a greater proportion of BDNF+/Met-enk+ mossy fiber boutons (MFBs) profiles (Figure 1H)
Summary
Proper hippocampal function depends on a finely-tuned balance between excitation and inhibition within the neuronal network, where any changes to this setting can have secondary effects on events such as protein synthesis and structural organization. It is assumed that many functions of Bsn are abrogated in this mutant, with major effects on synaptic transmission that manifest phenotypically as episodic generalized seizures in mature mutant mice (Altrock et al, 2003; Ghiglieri et al, 2009). This renders the Bsn-mutant mouse model as a means by which to monitor the effects of perturbed neuronal network activity. In addition to the changes in synaptic function, macroscopic analyses of the Bsnmutant brain have demonstrated functional and structural alterations to cortical structures. Manganese-enhanced magnetic resonance (MR) imaging and metabolic labeling with [14C]2D-deoxyglucose revealed altered cortical activation patterns in Bsn-mutant mice (Angenstein et al, 2007), while a follow-up MR spectroscopy study uncovered a reduction in neuronal
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