Environment geometry alters subiculum boundary vector cell receptive fields in adulthood and early development.

Boundaries to movement form a specific class of landmark information used for navigation: Boundary Vector Cells (BVCs) are neurons which encode an animal's location as a vector displacement from boundaries. Here we characterise the prevalence and spatial tuning of subiculum BVCs in adult and developing male rats, and investigate the relationship between BVC spatial firing and boundary geometry. BVC directional tunings align with environment walls in squares, but are uniformly distributed in circles, demonstrating that environmental geometry alters BVC receptive fields. Inserted barriers uncover both excitatory and inhibitory components to BVC receptive fields, demonstrating that inhibitory inputs contribute to BVC field formation. During post-natal development, subiculum BVCs mature slowly, contrasting with the earlier maturation of boundary-responsive cells in upstream Entorhinal Cortex. However, Subiculum and Entorhinal BVC receptive fields are altered by boundary geometry as early as tested, suggesting this is an inherent feature of the hippocampal representation of space.

Coordinated Emergence of Hippocampal Replay and Theta Sequences during Post-natal Development.

Hippocampal place cells encode an animal's current position in space during exploration [1]. During sleep, hippocampal network activity recapitulates patterns observed during recent experience: place cells with overlapping spatial fields show a greater tendency to co-fire ("reactivation") [2], and temporally ordered and compressed sequences of place cell firing observed during wakefulness are reinstated ("replay") [3-5]. Reactivation and replay may underlie memory consolidation [6-10]. Compressed sequences of place cell firing also occur during exploration: during each cycle of the theta oscillation, the set of active place cells shifts from those signaling positions behind to those signaling positions ahead of an animal's current location [11, 12]. These "theta sequences" have been linked to spatial planning [13]. Here, we demonstrate that, before weaning (post-natal day [P]21), offline place cell activity associated with sharp-wave ripples (SWRs) reflects predominantly stationary locations in recently visited environments. By contrast, sequential place cell firing, describing extended trajectories through space during exploration (theta sequences) and subsequent rest (replay), emerge gradually after weaning in a coordinated fashion, possibly due to a progressive decrease in the threshold for experience-driven plasticity. Hippocampus-dependent learning and memory emerge late in altricial mammals [14-17], appearing around weaning in rats and slowly maturing thereafter [14,15]. In contrast, spatially localized firing is observed 1 week earlier (with reduced spatial tuning and stability) [18-21]. By examining the development of hippocampal reactivation, replay, and theta sequences, we show that the coordinated maturation of offline consolidation and online sequence generation parallels the late emergence of hippocampal memory in the rat.

Effects of rising amyloidß levels on hippocampal synaptic transmission, microglial response and cognition in APPSwe/PSEN1M146V transgenic mice.

BACKGROUND: Progression of Alzheimer's disease is thought initially to depend on rising amyloidß and its synaptic interactions. Transgenic mice (TASTPM; APPSwe/PSEN1M146V) show altered synaptic transmission, compatible with increased physiological function of amyloidß, before plaques are detected. Recently, the importance of microglia has become apparent in the human disease. Similarly, TASTPM show a close association of plaque load with upregulated microglial genes. METHODS: CA1 synaptic transmission and plasticity were investigated using in vitro electrophysiology. Microglial relationship to plaques was examined with immunohistochemistry. Behaviour was assessed with a forced-alternation T-maze, open field, light/dark box and elevated plus maze. FINDINGS: The most striking finding is the increase in microglial numbers in TASTPM, which, like synaptic changes, begins before plaques are detected. Further increases and a reactive phenotype occur later, concurrent with development of larger plaques. Long-term potentiation is initially enhanced at pre-plaque stages but decrements with the initial appearance of plaques. Finally, despite altered plasticity, TASTPM have little cognitive deficit, even with a heavy plaque load, although they show altered non-cognitive behaviours. INTERPRETATION: The pre-plaque synaptic changes and microglial proliferation are presumably related to low, non-toxic amyloidß levels in the general neuropil and not directly associated with plaques. However, as plaques grow, microglia proliferate further, clustering around plaques and becoming phagocytic. Like in humans, even when plaque load is heavy, without development of neurofibrillary tangles and neurodegeneration, these alterations do not result in cognitive deficits. Behaviours are seen that could be consistent with pre-diagnosis changes in the human condition. FUNDING: GlaxoSmithKline; BBSRC; UCL; ARUK; MRC.

A Developmental Switch in Place Cell Accuracy Coincides with Grid Cell Maturation.

Place cell firing relies on information about self-motion and the external environment, which may be conveyed by grid and border cells, respectively. Here, we investigate the possible contributions of these cell types to place cell firing, taking advantage of a developmental time window during which stable border cell, but not grid cell, inputs are available. We find that before weaning, the place cell representation of space is denser, more stable, and more accurate close to environmental boundaries. Boundary-responsive neurons such as border cells may, therefore, contribute to stable and accurate place fields in pre-weanling rats. By contrast, place cells become equally stable and accurate throughout the environment after weaning and in adulthood. This developmental switch in place cell accuracy coincides with the emergence of the grid cell network in the entorhinal cortex, raising the possibility that grid cells contribute to stable place fields when an organism is far from environmental boundaries.

The development of spatial behaviour and the hippocampal neural representation of space.

The role of the hippocampal formation in spatial cognition is thought to be supported by distinct classes of neurons whose firing is tuned to an organism's position and orientation in space. In this article, we review recent research focused on how and when this neural representation of space emerges during development: each class of spatially tuned neurons appears at a different age, and matures at a different rate, but all the main spatial responses tested so far are present by three weeks of age in the rat. We also summarize the development of spatial behaviour in the rat, describing how active exploration of space emerges during the third week of life, the first evidence of learning in formal tests of hippocampus-dependent spatial cognition is observed in the fourth week, whereas fully adult-like spatial cognitive abilities require another few weeks to be achieved. We argue that the development of spatially tuned neurons needs to be considered within the context of the development of spatial behaviour in order to achieve an integrated understanding of the emergence of hippocampal function and spatial cognition.