The hippocampus lies deep within the medial temporal lobe of the brain and mediates critical functions related to emotional regulation, learning, memory, and cognitive functions. The primary cellular structure and hippocampal form is laid down in utero, 1 with postnatal development necessary for the full complement of cellular connections.2 Both anatomically and functionally, the hippocampus is a heterogeneous structure, with distinct subfields that differentially regulate learning, memory, and emotions. Common pregnancy complications, which include preterm birth, fetal growth restriction (FGR), intrauterine inflammation, and acute hypoxic-ischaemic insult at birth, can have profound effects on brain development and disrupt the hippocampus with life-long consequences for brain function. The rapid growth of the hippocampus during the third trimester of pregnancy, combined with its high neuronal density, renders it susceptible to injury in the event of intrauterine compromise.3,4 Magnetic resonance imaging (MRI) studies confirm that hippocampal structure is altered in human infants in response to perinatal compromise, with reduced hippocampal volume observed in children born preterm or growth restricted.3,5,6,7,8 A recent meta-analysis demonstrates that preterm-born individuals have smaller hippocampal volume compared to term-born individuals, even after accounting for differences in brain size, indicating that in utero compromise adversely impacts hippocampal growth.9 Additionally, pregnancy complications can lead to alterations in the connective pathways between the hippocampus and other brain regions. Subsequent to these structural alterations, short- and long-term functional consequences have been described, including problems in cognition, memory, and motor function.

The breadth of clinical and preclinical studies to examine normal and disrupted hippocampal development has necessitated a two-part review. Part one of this review is focused on normal hippocampal structure and function and provides available evidence from human studies that common perinatal insults disrupt hippocampal development. In the second part of this review10, we introduce the preclinical literature which describes the mechanisms underlying altered hippocampal form and function, including impaired neuronal morphology and synaptic connectivity.

Hippocampus is derived from the Greek terms for horse (hippo) and sea (kampos), reflecting the resemblance of this structure to a seahorse. It lies within the medial temporal lobe and forms part of the limbic system, regulating emotions, memory, cognitive function, spatial navigation, and motivational processes.11,12,13 The hippocampus comprises four cornu ammonis (CA) subfields (CA1, CA2, CA3 and CA4) and, together with the dentate gyrus (DG), subiculum and entorhinal cortex, is termed the hippocampal formation14,15,16 (Fig. 1). These regions of the hippocampal formation form a tightly connected circuit from the entorhinal cortex to the DG, and then into the CA subfields, with outputs from the subiculum to the thalamus, amygdala, hypothalamus, septum, and prefrontal cortex.15 The hippocampus is a neuron-rich, five-layer structure; a thin layer of white matter consisting of axons, the stratum alveus (ALV), a pyramidal neuronal layer, stratum pyramidale (SP) with basal dendrites extending to the stratum oriens (SO) and apical dendrites projecting into the stratum radiatum (SR), and stratum lacunosum moleculare (SL-M) layers (Fig. 1b). Supporting the pyramidal cells within the hippocampus are interneurons in the SO and SL-M layers, which are present in many different subtypes, however, all contribute to synaptic connections and cell signalling, and allow the intricacies of the hippocampal circuit to function appropriately.17,18,19

a Diagram depicting connectivity within the hippocampal region, and the connections to the entorhinal cortex (EC) layers (I-VI) and subcortical regions (i.e., thalamus, amygdala, hypothalamus). The distinct hippocampal subfields include the dentate gyrus (DG), Cornu ammonis (CA),1, CA2, CA3, and subiculum (S). b The hippocampus is comprised of five layers; stratum alveus (ALV) stratum oriens (SO), stratum pyramidale (SP), stratum radiatum (SR), and stratum lacunosum moleculare (SL-M). Imaged created with BioRender.com (agreement number YW266CRAY9).

Hippocampal development commences within weeks of conception and continues through the first years of life in human infants (Fig. 2). By week 8−9 of human gestation, the hippocampus is distinguishable from other brain regions, marking the beginning of distinct hippocampal development.2 The DG and CA begin as thin structures, and from 10 weeks’ gestation growth rate and thickness increase resulting in the folding of the DG and CA between 13 and 16 weeks’ gestation to form two interlocking C-shaped structures, in a process termed hippocampal inversion.2,20,21 Histological assessments from Humphrey20 formed the basis for many diagrammatic representations of hippocampal development during gestation, particularly describing this inversion, folding, and sulcation process. From the time of hippocampal inversion until approximately 20 weeks’ gestation represents a period of rapid growth, and it is said that the hippocampus develops faster than most other brain regions during this time, with peak neurogenesis occurring over this period.1 By 18 to 21 weeks’ gestation, the cellular foundations of the hippocampal formation are in place with the characteristic folded structure and sulcus present, with a near-full complement of pyramidal neurons.1,21 Thus, it is said that the hippocampus resembles the ‘adult’ form by mid-gestation in the human.1,21 Histological analysis of human fetal and infant hippocampal samples demonstrates that pyramidal neurons are primarily laid down in the first half of pregnancy.22

Dark solid colour indicates peak development, or time of insult.

The pyramidal neurons within the hippocampus align in an organised unidirectional formation along the pyramidale layer, residing within the five-layered structure from external to internal hippocampus; ALV, SO, SP, SR, and SL-M,23 with the pyramidal neuronal cell bodies sitting within the SP (Fig. 1). Interneurons reside within the SO and SL-M layers and support the connectivity and function of the pyramidal neurons. Formation of this five-layered structure occurs over a prolonged period in late gestation, with the pyramidal neurons following a “climbing” technique from the ventricular zone, where they are generated, to the SP layer, where they will reside. The climbing technique seen in the hippocampus differs from the typical migration of cortical and neocortical neurons24,25 and occurs due to the highly branched processes on the migrating hippocampal cells, which make contact with the radial fibres to allow a zig-zag motion through to the crowded SP layer.25 In the CA1 region, once the cell bodies of the pyramidal neurons reach their final destination within the SP, the neurons commence neurite outgrowth with basal dendrites extending into the ALV and SO, and apical dendrites projecting down into the SR and SL-M. The migration patterns of neurons within CA3 are thought to be similar to the CA1 neurons,24,26 however, less is known about the migration patterns of the other CA regions.

Mature pyramidal neurons have a highly arborised dendritic structure, which is an important determinant in the complexity of functions mediated by the hippocampus.27 Dendritogenesis of hippocampal neurons occurs from approximately mid-pregnancy in the human fetus and extends well into infancy.22 Structural analysis of CA3 hippocampal neurons in the human brain demonstrated that at 18 weeks’ gestation, both apical and basal dendrites were present but sparsely distributed, while at 33 weeks’ gestation, dendritic arborisation had increased 3-fold and showed a highly developed structure.28 Commencing days after a neuron has been generated, neurite sprouting commences, with one neurite extending in length to send the axon to the target area, while remaining neurites grow, extend and branch into the dendritic arbour for the establishment of synaptic connections.29 These synaptic connections between cells occur as membranous protrusions along the dendrites called spines. Spines are diverse in shape and length resulting in subtypes (filipodia, thin, stubby, mushroom spines) classification that develop along different timelines; filipodia are long and thin protrusions that exist transiently early in postnatal life and decrease into adulthood.30 Thin, stubby and mushroom spines are more stable with long-term potentiation, and regenerate throughout all stages of development, providing strong connections between synapses for optimal hippocampal function.30 Bourne and Harris31 describe an extensive list of molecular mediators (e.g., PSD-95, CamKII, Actin, N-cadherin) of spine development, stabilisation, and plasticity, highlighting the dynamic and adaptive nature of dendritic spines, which in the hippocampus is likely an important factor for structural and functional plasticity.

In Fig. 2, we broadly describe the developmental profile of the CA1 – CA3 regions. It is crucial, however, to appreciate the important role of the DG as the gateway of the hippocampus. Moreover, there are distinct structural and functional differences between the DG and the CA regions. For example, maturation of the DG occurs later than CA1 – CA3.32,33 The DG granule cell layer appears from the 12th week of gestation, with a high rate of cell proliferation from this timepoint through to the 24th week of pregnancy. From the 24th week of gestation, neurogenesis slows significantly but continues to about two years of age, where it then remains lifelong although at a diminished rate.2,33 One of the critical differences between the DG and the CA regions lies in the capacity of the DG for ongoing neurogenesis throughout life, with new neurons generated in the subgranular zone (SGZ) of the DG.34,35 Thus, the DG is considered to be a unique brain region as it holds a pool of neural stem cells that produce new neurons, contributing to brain plasticity and tissue regeneration.32 While knowledge gaps remain regarding the drivers and processes of adult neurogenesis, with likely some overlap between embryonic and adult neurogenesis, it is argued that lifelong neuronal regeneration is confined to the DG.36 The synaptic plasticity of DG hippocampal cells is regulated by activity and experiences that result in the formation of new memories and mediate DG neurogenesis.29 Interestingly, the granule cells of the DG are more resistant than pyramidal neurons of the CA1 to a number of adverse conditions,37,38 and therefore, the majority of the clinical research effort to date investigating hippocampal deficits has focussed on the CA regions.

The vasculature within the CA regions of the hippocampus is relatively sparse given the area of the hippocampus relative to other brain regions,39 with fewer, widely spaced microvessels, requiring oxygen to diffuse further into tissue.39 The lower vascular density is matched by a relatively low basal blood flow (~50% lower basal blood flow compared to the thalamus or brainstem).40 As would be expected, metabolic demand in the hippocampus matches the low vascular density and blood flow, with adjacent hippocampal pyramidal neurons not likely to be active simultaneously, reducing local energy demand compared to cortical regions.39 However, the low vascular density but neuron-rich population may explain the susceptibility of the hippocampus to perinatal compromise, as the sparse vasculature is not well suited to rapid adjustments in oxygen supply in response to a hypoxic insult.

The size, anatomical structure, and extensive connectivity within and external to the hippocampus are key to its heterogeneous functionality (Fig. 1). The axons that emanate from neurons in the entorhinal cortex synapse with dendrites of the granule cells of the DG, and axons from granule cells synapse with pyramidal cells in the CA3 region via hippocampal mossy fibres, an important pathway in memory formation.41 The hippocampal mossy fibres connect DG granule cells to CA3 pyramidal neurons allowing information to flow in a unidirectional manner to the CA1, and then extend out of the hippocampus proper via CA1 axons.15 The DG, therefore, provides a crucial gateway between the entorhinal cortex and the hippocampus proper, with DG neurons receiving the first input and passing information further along the pathway,41 with the entorhinal cortex mediating hippocampal communications, acting as the major input and output regulator.42 Multiple areas including the amygdaloid complex, medial septal region, and the thalamus, provide extrinsic inputs into the hippocampal circuitry, via the entorhinal cortex, as described by Papex.43 Distal to the CA1 region, the subiculum of the hippocampal formation is an anatomical transition zone (subiculum means support in Latin), and a major source for hippocampal output into the cortical regions of the brain, thereby directing activity across the brain.44

Interrogation of the CA1 pyramidal neuron structure within the hippocampal circuitry reveals the unique roles of the basal and apical dendrites. The apical dendrites receive inputs at various points along the dendrite, from the CA3 neurons via Schaffer collaterals at the proximal end to the soma, and direct glutamatergic input from the entorhinal cortex at the distal dendrites. Conversely, the basal dendrites receive direct inputs from CA2 neurons (Fig. 1).45,46,47,48 This is an important distinction to consider as there are examples of perinatal compromise that impact only the apical dendrites, impairing both connectivity and functionality of the neuron in a unique manner, compared to an insult that may affect basal dendrites.49

Compared to the intra-hippocampal microcircuitry, the extra-hippocampal connections are complex and not well characterised.50 In vivo assessment of hippocampal connections undertaken by Maller et al.50 revealed six predominant hippocampal pathways – the inferior longitudinal fasciculus, spinal-limbic pathway, anterior commissure, cingulate bundle, fornix and tapetum - all long-range pathways connecting limbic and sub-cortical structures. This connectivity reflects the wide-ranging functionality of the hippocampus and the ability of the hippocampus to moderate multiple brain processes.

The optimal function of the complex internal neuronal network of the hippocampus and the long-range extrinsic connections requires mature myelin. Myelin is the fatty insulation that surrounds the axons and aids the conduction velocity of neurons in the hippocampal pathways.51 The developmental profile of myelin within the hippocampus, described by Abraham et al.,52 begins at 20 weeks’ gestation with the presence of mature oligodendrocytes and myelinated axons appearing in the hippocampal region between 21-35 weeks. Myelination extends well past birth until adult-like myelin density is present in adolescent tissue,52,53 consequent with an increase in hippocampal volume over this period.54 It is not yet understood when myelination ceases, however, the increase in hippocampal volume that occurs in childhood is followed by stabilisation or subtle subfield decreases at adolescence, suggesting that adolescence may be the timepoint where myelination is complete.54

Functional assessments of the hippocampus have a rich and well-documented history. Famously, the 1953 case of H.M., who lost much of his memory when his hippocampus was removed in an attempt to treat epilepsy, provided the first insight into the primary functions of the hippocampus.55 Since then, research has taken great strides to elucidate the function of the hippocampus, including the differential roles of the component sub-regions. The intrinsic circuitry of the hippocampus, as well as the vast connections to cortical and subcortical brain regions, gives rise to multiple functions that span episodic memory, emotional regulation, spatial navigation, learning, and cognition. Further, the distinct structure and connections of the anterior and posterior hippocampus have been shown to underpin separate functional roles, however, this is still to be fully elucidated.56 The posterior hippocampus is described as playing a more significant regulatory role in spatial memory as it receives visual and spatial information from the anterior cingulate cortex.12,56,57 In contrast, the anterior hippocampus has strong connections with the prefrontal cortex, amygdala, and hypothalamus, favouring emotional processing and autonomic endocrine systems.12,58 To date, there is little research that separates the anterior from the posterior hippocampus in the context of hippocampal dysfunction or injury during fetal and neonatal development.

Many functions of the hippocampus, including learning, memory, and spatial navigation, are facilitated by long-term potentiation (LTP),59,60,61,62 which is the persistent strengthening of synapses that fosters signal transmission between neurons. Long-term potentiation is widely recognised as the cellular mechanism of memory formation.63 Within the hippocampus, LTP is shown to regulate hippocampal plasticity with glutamate receptors such as α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) or N-methyl-D-aspartate (NMDA) integral to this role.64 It is these receptors that drive synaptic plasticity, promote LTP, and allow for wide-ranging functionality of the hippocampus. Neuropeptides also play a key role in supporting the neurotransmitters within the hippocampus; somatostatin is one neuropeptide known to significantly contribute to emotion regulation signals.65

Brain development over the perinatal period is sensitive to disruptions arising from common pregnancy complications, including preterm birth, FGR, and hypoxic-ischaemic encephalopathy (HIE).66,67,68,69 The strong association between perinatal compromise and structural abnormalities of the hippocampus is evident from clinical studies linking brain imaging outcomes with functional deficits. Key milestones in hippocampal development such as neuronal migration, neurite outgrowth of axons and dendrites, and synaptogenesis are highly active from about mid-pregnancy (20 weeks’ gestation) onwards (Fig. 2), therefore, preterm birth or other complications during pregnancy will significantly disrupt these developmental processes. Further, as the hippocampus is still developing at term, insults occurring around the time of birth, such as perinatal (birth) asphyxia resulting in HIE, can also cause damage.

Preterm birth affects approximately 11% of births worldwide and results in significant perturbations in brain development.70 Preterm birth can be sub-categorised as extremely preterm (<28 weeks gestation (GA)), very preterm (28–32 weeks GA) and moderate to late preterm (32−37 weeks GA).71 There is a multitude of factors and complications that can arise during pregnancy to induce preterm birth including having had a previous premature baby, twin/multiple pregnancy, intrauterine infection, substance abuse, premature rupture of membranes, or impaired development of the baby indicating early delivery.72 Numerous studies show that neuropathology associated with the preterm brain is principally via two relatively common upstream insults, hypoxia-ischaemia (HI) and infection/inflammation.69,73 Intrauterine inflammation, including placental and amniotic fluid infection (chorioamnionitis), is recognised as a causal factor that both predisposes to preterm birth,