Development and topographic organization of subicular projections to lateral septum in the rat brain

One of the main subcortical targets of hippocampal formation efferents is the lateral septum. Previous studies on the subicular projections, as a main output structure of the hippocampus, have shown a clear topographic organization of septal innervation, related to the origin of the fibres along the dorsoventral axis of the subiculum in the adult brain. In contrast, studies on the developing brain depict an extensive rearrangement of subicular projections during the prenatal period, shifting from the medial septum to the lateral septum. Our study aimed to describe the postnatal development of subicular projections to the septum. We injected anterograde tracers into the subiculum of 57 pups of different postnatal ages. Injections covered the proximodistal and dorsoventral axis of the subiculum. The age of the pups at day of tracer injection ranged from the day of birth to postnatal day 30. Analyses revealed that from the first postnatal day projections from subiculum preferentially target the lateral septum. Sparse innervation in the lateral septum was already present in the first few postnatal days, and during the following 3 weeks, the axonal distribution gradually expanded. Subicular projections to the lateral septum are topographically organized depending on the origin along the dorsoventral axis of the subiculum, in line with the adult innervation pattern. Different origins along the proximodistal axis of the subiculum are reflected in changes in the strength of septal innervation. The findings demonstrate that in case of the development of subicular projections, axonal expansion is more prominent than axonal pruning

Convergent projections from perirhinal and postrhinal cortices suggest a multisensory nature of lateral but not medial entorhinal cortex

The current model of the organization of the medial temporal lobe (MTL) episodic memory system assumes that two functionally different “where” and “what” pathways enter MTL as parallel parahippocampal cortex (PHC)-medial entorhinal cortex (MEC) and perirhinal cortex (PER)-lateral entorhinal cortex (LEC) streams, respectively. With the use of tract tracing and in vitro electrophysiological recordings, we show that, in the rat LEC, all main principal neuron types in layer II receive convergent inputs from PER and postrhinal cortex (POR), homologous to PHC in primates. Projections to MEC from POR are much less prominent than previously assumed. These findings thus challenge the prevailing concept that LEC and MEC are defined by different inputs from the PER and PHC/POR, respectively. Our findings point to LEC as the main parahippocampal multimodal integrative structure whose unique set of external sensory-derived inputs allows its network to represent a continuously fluctuating extrinsic environment

Re-emphasizing early Alzheimer's disease pathology starting in select entorhinal neurons, with a special focus on mitophagy

The entorhinal-hippocampal system contains distinct networks subserving declarative memory. This system is selectively vulnerable to changes of ageing and pathological processes. The entorhinal cortex (EC) is a pivotal component of this memory system since it serves as the interface between the neocortex and the hippocampus. EC is heavily affected by the proteinopathies of Alzheimer’s disease (AD). These appear in a stereotypical spatiotemporal manner and include increased levels of intracellular amyloid-beta Aβ (iAβ), parenchymal deposition of Aβ plaques, and neurofibrillary tangles (NFTs) containing abnormally processed Tau. Increased levels of iAβ and the formation of NFTs are seen very early on in a population of neurons belonging to EC layer II (EC LII), and recent evidence leads us to believe that this population is made up of highly energy-demanding reelin-positive (RE+) projection neurons. Mitochondria are fundamental to the energy supply, metabolism, and plasticity of neurons. Evidence from AD postmortem brain tissues supports the notion that mitochondrial dysfunction is one of the initial pathological events in AD, and this is likely to take place in the vulnerable RE + EC LII neurons. Here we review and discuss these notions, anchored to the anatomy of AD, and formulate a hypothesis attempting to explain the vulnerability of RE + EC LII neurons to the formation of NFTs. We attempt to link impaired mitochondrial clearance to iAβ and signaling involving both apolipoprotein 4 and reelin, and argue for their relevance to the formation of NFTs specifically in RE + EC LII neurons during the prodromal stages of AD. We believe future studies on these interactions holds promise to advance our understanding of AD etiology and provide new ideas for drug development

Postnatal Development of Functional Projections from Parasubiculum and Presubiculum to Medial Entorhinal Cortex in the Rat

Neurons in parasubiculum (PaS), presubiculum (PrS), and medial entorhinal cortex (MEC) code for place (grid cells) and head direction. Directional input has been shown to be important for stable grid cell properties in MEC, and PaS and PrS have been postulated to provide this information to MEC. In line with this, head direction cells in those brain areas are present at postnatal day 11 (P11), having directional tuning that stabilizes shortly after eye opening, which is before premature grid cells emerge in MEC at P16. Whether functional connectivity between these structures exists at those early postnatal stages is unclear. Using anatomical tracing, voltage-sensitive dye imaging and single-cell patch recordings in female and male rat brain slices between P2 and P61, we determined when the pathways from PaS and PrS to MEC emerge, become functional, and how they develop. Anatomical connections from PaS and PrS to superficial MEC emerge between P4 and P6. Monosynaptic connectivity from PaS and PrS to superficial MEC was measurable from P9 to P10 onward, whereas connectivity with deep MEC was measurable from P11 to P12. From P14/P15 on, reactivity of MEC neurons to parasubicular and presubicular inputs becomes adult-like and continues to develop until P28-P30. The maturation of the efficacy of both inputs between P9 and P21 is paralleled by maturation of morphological properties, changes in intrinsic properties of MEC principal neurons, and changes in the GABAergic network of MEC. In conclusion, synaptic projections from PaS and PrS toMEC become functional and adult-like before the emergence of grid cells in MEC

Re-emphasizing early Alzheimer's disease pathology starting in select entorhinal neurons, with a special focus on mitophagy

The entorhinal-hippocampal system contains distinct networks subserving declarative memory. This system is selectively vulnerable to changes of ageing and pathological processes. The entorhinal cortex (EC) is a pivotal component of this memory system since it serves as the interface between the neocortex and the hippocampus. EC is heavily affected by the proteinopathies of Alzheimer’s disease (AD). These appear in a stereotypical spatiotemporal manner and include increased levels of intracellular amyloid-beta Aβ (iAβ), parenchymal deposition of Aβ plaques, and neurofibrillary tangles (NFTs) containing abnormally processed Tau. Increased levels of iAβ and the formation of NFTs are seen very early on in a population of neurons belonging to EC layer II (EC LII), and recent evidence leads us to believe that this population is made up of highly energy-demanding reelin-positive (RE+) projection neurons. Mitochondria are fundamental to the energy supply, metabolism, and plasticity of neurons. Evidence from AD postmortem brain tissues supports the notion that mitochondrial dysfunction is one of the initial pathological events in AD, and this is likely to take place in the vulnerable RE + EC LII neurons. Here we review and discuss these notions, anchored to the anatomy of AD, and formulate a hypothesis attempting to explain the vulnerability of RE + EC LII neurons to the formation of NFTs. We attempt to link impaired mitochondrial clearance to iAβ and signaling involving both apolipoprotein 4 and reelin, and argue for their relevance to the formation of NFTs specifically in RE + EC LII neurons during the prodromal stages of AD. We believe future studies on these interactions holds promise to advance our understanding of AD etiology and provide new ideas for drug development

Neuropeptides in the developing human hippocampus under hypoxic–ischemic conditions

The perinatal period, sensitive for newborn survival, is also one of the most critical moments in human brain development. Perinatal hypoxia due to reduced blood supply to the brain (ischemia) is one of the main causes of neonatal mortality. Brain damage caused by perinatal hypoxia–ischemia (HI) can lead to neuro- and psychological disorders. However, its impact seems to be region-dependent, with the hippocampus being one of the most affected areas. Among the neuronal populations of the hippocampus, some interneuron groups – such as somatostatin- or neuropeptide Y-expressing neurons – seem to be particularly vulnerable. The limited information available about the effects of HI in the hippocampus comes mainly from animal models and adult human studies. This article presents an immunohistochemical analysis of somatostatin (SOM) and neuropeptide Y (NPY) expression in the developing human hippocampus after perinatal HI. Two rostrocaudal sections of the body of the hippocampus were analysed, and the number of immunostained cells in the polymorphic layer of the dentate gyrus (DG) and the pyramidal cell layer and stratum oriens of the CA3, CA2 and CA1 fields of the hippocampus proper were quantified. The results showed a lower density of both neuropeptides in hypoxic compared to control cases. In the HI group, the number of SOM-immunoreactive cell bodies was statistically significantly lower in the pyramidal cell layer and stratum oriens of CA1, while the number of NPY-expressing neurons was statistically lower in the pyramidal cell layer of CA2. Besides, the number of SOM-expressing neurons was significantly higher in the stratum oriens of CA1 compared to that in CA2. In sum, we observed a different vulnerability of SOM- and NPY-containing neurons in the developing human hippocampus following perinatal HI damage. Our results could contribute to a better understanding of the behaviour of these neuronal populations under stressful conditions during the perinatal period