Hippocampal enlargement in Bassoon-mutant mice is associated with enhanced neurogenesis, reduced apoptosis, and abnormal BDNF levels

Abstract

Mice mutant for the presynaptic protein Bassoon develop epileptic seizures and an altered pattern of neuronal activity that is accompanied by abnormal enlargement of several brain structures, with the strongest size increase in hippocampus and cortex. Using manganese-enhanced magnetic resonance imaging, an abnormal brain enlargement was found, which is first detected in the hippocampus 1 month after birth and amounts to an almost 40% size increase of this structure after 3 months. Stereological quantification of cell numbers revealed that enlargement of the dentate gyrus and the hippocampus proper is associated with larger numbers of principal neurons and of astrocytes. In search for the underlying mechanisms, an approximately 3-fold higher proportion of proliferation and survival of new-born cells in the dentate gyrus was found to go hand in hand with similarly larger numbers of doublecortin-positive cells and reduced numbers of apoptotic cells in the dentate gyrus and the hippocampus proper. Enlargement of the hippocampus and of other forebrain structures was accompanied by increased levels of brain-derived neurotrophic factor (BDNF). These data show that hippocampal overgrowth in Bassoon-mutant mice arises from a dysregulation of neurogenesis and apoptosis that might be associated with unbalanced BDNF levels.

Fingolimod, a sphingosine-1 phosphate receptor modulator, increases BDNF levels and improves symptoms of a mouse model of Rett syndrome

“…BDNF sandwich ELISA was performed as described (14,45), except that bovine serum albumin was omitted from the extraction buffer.…”

The Presynaptic Active Zone

“…In synapses with a partial loss of both piccolo and bassoon, synaptic vesicle clusters are disrupted, indicating a possible role for these proteins in vesicle clustering (Mukherjee et al, 2010). Given the size of piccolo and bassoon, the interesting C-terminal domains of piccolo, and the reactive changes observed in bassoon knockout mice (Heyden et al, 2011), it seems likely that the more peripheral active zone function of piccolo and bassoon will have an important role in overall brain performance. This role may be particularly important in specialized synapses such as hippocampal mossy fiber synapses or retinal ribbon synapses.…”

Hippocampal Volume in Type 1 Diabetes

“…In animal studies, knocking out a presynaptic scaffolding protein can result in a significantly larger hippocampus. 57 While this presynaptic protein may not be relevant to hypoglycemia, this study did find that the enlarged volume was due to uncontrolled neurogenesis and gliosis, seen by an increase in the number of both neurons and glia, as well as reduced cell death and an increase in brain-derived neurotrophic factor (BDNF). 57 Brain insults, such as severe hypoglycemia, have been shown to increase expression of BDNF and other growth factors, 58 likely as a compensatory mechanism, and levels of these neurotrophic factors fluctuate throughout development with neurogenesis and are particularly high in the hippocampus.…”

“…57 While this presynaptic protein may not be relevant to hypoglycemia, this study did find that the enlarged volume was due to uncontrolled neurogenesis and gliosis, seen by an increase in the number of both neurons and glia, as well as reduced cell death and an increase in brain-derived neurotrophic factor (BDNF). 57 Brain insults, such as severe hypoglycemia, have been shown to increase expression of BDNF and other growth factors, 58 likely as a compensatory mechanism, and levels of these neurotrophic factors fluctuate throughout development with neurogenesis and are particularly high in the hippocampus. 59 63 however, in an adolescent population, these two factors were not associated which may indicate age-dependent effects from chronic exposure to hyperglycemia on the hippocampus.…”