Abstract
The dentate gyrus is the primary afferent into the hippocampal formation, with important functions in learning and memory. Granule cells, the principle neuronal type in the dentate gyrus, are mostly formed postnatally, in a process that continues into adulthood. External stimuli, including environmental enrichment, voluntary exercise and learning, have been shown to significantly accelerate the generation and maturation of dentate granule cells in adult rodents. Whether, and to what extent, such environmental stimuli regulate the development and maturation of dentate granule cells during early postnatal development is largely unknown. Furthermore, whether natural stimuli affect the synaptic properties of granule cells had been investigated neither in newborn neurons of the adult nor during early development. To examine the effect of natural sensory stimulation on the dentate gyrus, we reared newborn mice in an enriched environment (EE). Using immunohistochemistry, we showed that dentate granule cells from EE-reared mice exhibited earlier morphological maturation, manifested as faster peaking of doublecortin expression and elevated expression of mature neuronal markers (including NeuN, calbindin and MAP2) at the end of the second postnatal week. Also at the end of the second postnatal week, we found increased density of dendritic spines across the entire dentate gyrus, together with elevated levels of postsynaptic scaffold (post-synaptic density 95) and receptor proteins (GluR2 and GABAARγ2) of excitatory and inhibitory synapses. Furthermore, dentate granule cells of P14 EE-reared mice had lower input resistances and increased glutamatergic and GABAergic synaptic inputs. Together, our results demonstrate that EE-rearing promotes morphological and electrophysiological maturation of dentate granule cells, underscoring the importance of natural environmental stimulation on development of the dentate gyrus.
Highlights
The dentate gyrus is one of two main locations of continuous neurogenesis in the adult rodent brain [1,2]
Biochemical and electrophysiological assays, we showed that this paradigm significantly accelerated morphological and functional maturation of dentate granule cells during the first two postnatal weeks, slowly plateauing by the end of the third postnatal week
To determine whether our environmental enrichment paradigm significantly elevated neuronal activity in the dentate gyrus of newborn mice, we assayed the protein level of two well known activity-induced genes, namely brain-derived neurotrophic factor BDNF [25,26,27] and the immediate early gene c-fos [28]. The level of both proteins was found to be significantly elevated in extracts from the dentate gyrus of P7 and P14 EE-reared mice, as compared to those reared in standard control cages (Figure 1), demonstrating the effectiveness of our paradigm in elevating neuronal activity in vivo
Summary
The dentate gyrus is one of two main locations of continuous neurogenesis in the adult rodent brain [1,2]. Of mutants that survived into adulthood, mice lacking the transcription factor NeuroD, with relatively specific defects in the differentiation of dentate granule cells [12,13], displayed spontaneous limbic seizures [13] In another example, mice mutant for Frizzled 9, a gene in the Williams syndrome deletion interval, with increased apoptosis of dentate granule cells during development, had diminished seizure threshold and severe deficits in tests of visuospatial learning and memory [14]. Mice mutant for Frizzled 9, a gene in the Williams syndrome deletion interval, with increased apoptosis of dentate granule cells during development, had diminished seizure threshold and severe deficits in tests of visuospatial learning and memory [14] These examples pinpoint the importance of dentate gyrus development for normal brain function and plasticity
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