Transcriptional development of the hippocampus and the dorsal-intermediate-ventral axis in rats

Risk and resilience for neuropsychiatric illnesses are established during brain development, and transcriptional markers of risk may be identifiable in early development. The dorsal-ventral axis of the hippocampus has behavioral, electrophysiological, anatomical, and transcriptional gradients and abnormal hippocampus development is associated with autism, schizophrenia, epilepsy, and mood disorders. We previously showed that differential gene expression along the dorsoventral hippocampus in rats was present at birth (postnatal day 0, P0), and that a subset of differentially expressed genes (DEGs) was present at all postnatal ages examined (P0, P9, P18, and P60). Here, we extend the analysis of that gene expression data to understand the development of the hippocampus as a whole by examining DEGs that change with age. We additionally examine development of the dorsoventral axis by looking at DEGs along the axis at each age. Using both unsupervised and supervised analyses, we find that the majority of DEGs are present from P0 to P18, with many expression profiles presenting peaks or dips at P9/18. During development of the hippocampus, enriched pathways associated with learning, memory, and cognition increase with age, as do pathways associated with neurotransmission and synaptic function. Development of the dorsoventral axis is greatest at P9 and P18 and is marked by DEGs associated with metabolic functions. Our data indicate that neurodevelopmental disorders like epilepsy, schizophrenia and affective disorders are enriched with developmental DEGs in the hippocampus, regardless of dorsoventral location, with the greatest enrichment of these clinical disorders seen in genes whose expression changes from P0-9. When comparing DEGs from the ventral and dorsal poles, the greatest number of neurodevelopmental disorders is enriched with DEGs found at P18. Taken together, the developing hippocampus undergoes substantial transcriptional maturation during early postnatal development, with expression of genes involved in neurodevelopmental disorders also showing maximal expression changes within this developmental period.