Region-specific dendritic simplification induced by Aβ, mediated by tau via dysregulation of microtubule dynamics: a mechanistic distinct event from other neurodegenerative processes.

BackgroundDendritic simplification, a key feature of the neurodegenerative triad of Alzheimer's disease (AD) in addition to spine changes and neuron loss, occurs in a region-specific manner. However, it is unknown how changes in dendritic complexity are mediated and how they relate to spine changes and neuron loss.ResultsTo investigate the mechanisms of dendritic simplification in an authentic CNS environment we employed an ex vivo model, based on targeted expression of enhanced green fluorescent protein (EGFP)-tagged constructs in organotypic hippocampal slices of mice. Algorithm-based 3D reconstruction of whole neuron morphology in different hippocampal regions was performed on slices from APPSDL-transgenic and control animals. We demonstrate that induction of dendritic simplification requires the combined action of amyloid beta (Aβ) and human tau. Simplification is restricted to principal neurons of the CA1 region, recapitulating the region specificity in AD patients, and occurs at sites of Schaffer collateral input. We report that γ-secretase inhibition and treatment with the NMDA-receptor antagonist, CPP, counteract dendritic simplification. The microtubule-stabilizing drug epothilone D (EpoD) induces simplification in control cultures per se. Similar morphological changes were induced by a phosphoblocking tau construct, which also increases microtubule stability. In fact, low nanomolar concentrations of naturally secreted Aβ decreased phosphorylation at S262 in a cellular model, a site which is known to directly modulate tau-microtubule interactions.ConclusionsThe data provide evidence that dendritic simplification is mechanistically distinct from other neurodegenerative events and involves microtubule stabilization by dendritic tau, which becomes dephosphorylated at certain sites. They imply that treatments leading to an overall decrease of tau phosphorylation might have a negative impact on neuronal connectivity

Hippocampal subregion abnormalities in schizophrenia: A systematic review of structural and physiological imaging studies.

AimThe hippocampus is considered a key region in schizophrenia pathophysiology, but the nature of hippocampal subregion abnormalities and how they contribute to disease expression remain to be fully determined. This study reviews findings from schizophrenia hippocampal subregion volumetric and physiological imaging studies published within the last decade.MethodsThe PubMed database was searched for publications on hippocampal subregion volume and physiology abnormalities in schizophrenia and their findings were reviewed.ResultsThe main replicated findings include smaller CA1 volumes and CA1 hyperactivation in schizophrenia, which may be predictive of conversion in individuals at clinical high risk of psychosis, smaller CA1 and CA4/DG volumes in first-episode schizophrenia, and more widespread smaller hippocampal subregion volumes with longer duration of illness. Several studies have reported relationships between hippocampal subregion volumes and declarative memory or symptom severity.ConclusionsTogether these studies provide support for hippocampal formation circuitry models of schizophrenia. These initial findings must be taken with caution as the scientific community is actively working on hippocampal subregion method improvement and validation. Further improvements in our understanding of the nature of hippocampal formation subregion involvement in schizophrenia will require the collection of structural and physiological imaging data at submillimeter voxel resolution, standardization and agreement of atlases, adequate control for possible confounding factors, and multi-method validation of findings. Despite the need for cautionary interpretation of the initial findings, we believe that improved localization of hippocampal subregion abnormalities in schizophrenia holds promise for the identification of disease contributing mechanisms

Synaptic Plasticity and Memory: New Insights from Hippocampal Left-Right Asymmetries.

All synapses are not the same. They differ in their morphology, molecular constituents, and malleability. A striking left-right asymmetry in the distribution of different types of synapse was recently uncovered at the CA3-CA1 projection in the mouse hippocampus, whereby afferents from the CA3 in the left hemisphere innervate small, highly plastic synapses on the apical dendrites of CA1 pyramidal neurons, whereas those originating from the right CA3 target larger, more stable synapses. Activity-dependent modification of these synapses is thought to participate in circuit formation and remodeling during development, and further plastic changes may support memory encoding in adulthood. Therefore, exploiting the CA3-CA1 asymmetry provides a promising opportunity to investigate the roles that different types of synapse play in these fundamental properties of the CNS. Here we describe the discovery of these segregated synaptic populations in the mouse hippocampus, and discuss what we have already learnt about synaptic plasticity from this asymmetric arrangement. We then propose models for how the asymmetry could be generated during development, and how the adult hippocampus might use these distinct populations of synapses differentially during learning and memory. Finally, we outline the potential implications of this left-right asymmetry for human hippocampal function, as well as dysfunction in memory disorders such as Alzheimer's disease.The author's research was supported by the Biotechnology and Biological Sciences Research Council (BBSRC), UK. M.E-­G. is supported by a BBSRC Studentship.This is the author accepted manuscript. The final version is available from Sage via http://dx.doi.org/10.1177/107385841455065

Segmenting subregions of the human hippocampus on structural magnetic resonance image scans: An illustrated tutorial

BACKGROUND: The hippocampus plays a central role in cognition, and understanding the specific contributions of its subregions will likely be key to explaining its wide-ranging functions. However, delineating substructures within the human hippocampus in vivo from magnetic resonance image scans is fraught with difficulties. To our knowledge, the extant literature contains only brief descriptions of segmentation procedures used to delineate hippocampal subregions in magnetic resonance imaging/functional magnetic resonance imaging studies. // METHODS: Consequently, here we provide a clear, step-by-step and fully illustrated guide to segmenting hippocampal subregions along the entire length of the human hippocampus on 3T magnetic resonance images. // RESULTS: We give a detailed description of how to segment the hippocampus into the following six subregions: dentate gyrus/Cornu Ammonis 4, CA3/2, CA1, subiculum, pre/parasubiculum and the uncus. Importantly, this in-depth protocol incorporates the most recent cyto- and chemo-architectural evidence and includes a series of comprehensive figures which compare slices of histologically stained tissue with equivalent 3T images. // CONCLUSION: As hippocampal subregion segmentation is an evolving field of research, we do not suggest this protocol is definitive or final. Rather, we present a fully explained and expedient method of manual segmentation which remains faithful to our current understanding of human hippocampal neuroanatomy. We hope that this 'tutorial'-style guide, which can be followed by experts and non-experts alike, will be a practical resource for clinical and research scientists with an interest in the human hippocampus

The Ontogeny of Hippocampus-Dependent Memories

The formation of memories that contain information about the specific time and place of acquisition, which are commonly referred to as "autobiographical" or "episodic" memories, critically relies on the hippocampus and on a series of interconnected structures located in the medial temporal lobe of the mammalian brain. The observation that adults retain very few of these memories from the first years of their life has fueled a long-standing debate on whether infants can make the types of memories that in adults are processed by the hippocampus-dependent memory system, and whether the hippocampus is involved in learning and memory processes early in life. Recent evidence shows that, even at a time when its circuitry is not yet mature, the infant hippocampus is able to produce long-lasting memories. However, the ability to acquire and store such memories relies on molecular pathways and network-based activity dynamics different from the adult system, which mature with age. The mechanisms underlying the formation of hippocampus-dependent memories during infancy, and the role that experience exerts in promoting the maturation of the hippocampus-dependent memory system, remain to be understood. In this review, we discuss recent advances in our understanding of the ontogeny and the biological correlates of hippocampus-dependent memories

Synaptic Plasticity and Hebbian Cell Assemblies

Synaptic dynamics are critical to the function of neuronal circuits on multiple timescales. In the first part of this dissertation, I tested the roles of action potential timing and NMDA receptor composition in long-term modifications to synaptic efficacy. In a computational model I showed that the dynamics of the postsynaptic [Ca2+] time course can be used to map the timing of pre- and postsynaptic action potentials onto experimentally observed changes in synaptic strength. Using dual patch-clamp recordings from cultured hippocampal neurons, I found that NMDAR subtypes can map combinations of pre- and postsynaptic action potentials onto either long-term potentiation (LTP) or depression (LTD). LTP and LTD could even be evoked by the same stimuli, and in such cases the plasticity outcome was determined by the availability of NMDAR subtypes. The expression of LTD was increasingly presynaptic as synaptic connections became more developed. Finally, I found that spike-timing-dependent potentiability is history-dependent, with a non-linear relationship to the number of pre- and postsynaptic action potentials. After LTP induction, subsequent potentiability recovered on a timescale of minutes, and was dependent on the duration of the previous induction. While activity-dependent plasticity is putatively involved in circuit development, I found that it was not required to produce small networks capable of exhibiting rhythmic persistent activity patterns called reverberations. However, positive synaptic scaling produced by network inactivity yielded increased quantal synaptic amplitudes, connectivity, and potentiability, all favoring reverberation. These data suggest that chronic inactivity upregulates synaptic efficacy by both quantal amplification and by the addition of silent synapses, the latter of which are rapidly activated by reverberation. Reverberation in previously inactivated networks also resulted in activity-dependent outbreaks of spontaneous network activity. Applying a model of short-term synaptic dynamics to the network level, I argue that these experimental observations can be explained by the interaction between presynaptic calcium dynamics and short-term synaptic depression on multiple timescales. Together, the experiments and modeling indicate that ongoing activity, synaptic scaling and metaplasticity are required to endow networks with a level of synaptic connectivity and potentiability that supports stimulus-evoked persistent activity patterns but avoids spontaneous activity

Impact of environmental risk factors for schizophrenia on the developing brain, characterisation of the effects of polyIC and THC on functional neural systems and behaviour

Strathclyde theses - ask staff. Thesis no. : T13455Cannabis abuse can produce deficits in cognition and has been implicated as a 'late' environmental risk factor in the pathogenesis of the poly-factorial disorder schizophrenia. Evidence suggests an age-related susceptibility to the deleterious effects of cannabis as early onset of use may increase the vulnerability of the brain to the adverse consequences of cannabis abuse. Animal models are crucial for exploration of mechanistic and causative theories, and long-term behavioural consequences of adolescent cannabis abuse in a controlled experimental environment. This thesis evaluates the vulnerability of the adolescent/peripubertal brain to Δ9-tetrahydrocannabinol (THC), the principal psychoactive constituent of cannabis, and explores the potential interplay between this schizophrenia-related 'late' environmental risk factor and an 'early' environmental risk factor (prenatal infection - maternal immune activation (MIA)) on functional neural systems and behaviours relevant to schizophrenia. Cannabinoid CB1 receptor ontogeny (activated in the brain by the receptor ligand THC) within important cognitive substrates, the prefrontal cortex (PFC) and hippocampus, was investigated to delineate a period of neurodevelopmental vulnerability for peripubertal THC treatment. CB1 receptor ligand binding revealed that the PFC and hippocampus follow differential late maturational trajectories throughout the peripubertal period. The 'vulnerability window' for peripubertal THC treatment was defined as post-natal day (PD) 35-56 to encompass the dynamic peripubertal ontogenetic patterns of the CB1 receptor in both these regions. Furthermore, age-related alterations in cerebral metabolism and regional functional connectivity profiles were evident in the hippocampus and important neuromodulatory nuclei including the ventral tegmental area, dorsal raphe, locus coeruleus and the diagonal band of Broca.;Acute THC administration (5mg/kg) produced hypometabolism in the thalamus and an altered functional connectivity profile between thalamic nuclei and the PFC, hippocampus and the nucleus accumbens. THC-induced anomalistic neural activity was evident in key neuromodulatory nuclei and produced perturbed functional connectivity within acetylcholine, noradrenaline, and dopamine neural pathways. Acute THC treatment resulted in alterations in cerebral metabolism in the amygdala and aberrant functional connectivity profiles between amygdaloid nuclei and the hippocampus, PFC and nucleus accumbens. There appeared to be an age-related sensitivity to THC in several thalamic, neuromodulatory and amygdaloid nuclei. Peripubertal low-dose intermittent THC (3.5mg/kg, 3 times a week), mimetic of light, recreational adolescent cannabis use, produced long-term cognitive inflexibility, as measured by the attentional-set shifting task, perturbed cerebral metabolism in the dorsolateral orbital cortex and the nucleus accumbens core and altered functional coupling between both these regions and neural substrates subserving reward-related learning including prefrontal, septal and amygdala subfields. High-dose daily THC (7mg/kg) throughout the peripubertal period, mimetic of heavy daily cannabis abuse, did not precipitate any schizophrenia-related behaviours in adulthood. MIA induced by prenatal exposure to the immune-stimulating agent polyriboinosinic-polyribocytidilic acid (PolyIC) did not produce any schizophrenia-related phenotypes in adulthood. However, prenatal PolyIC exposure produced residual hypermetabolism within discrete components of the prefrontal cortex dorsolateral orbital and cingulate cortices and hypometabolism within the CA3 subfield of the hippocampus. The functional connectivity signatures of all these regions indicated a unified MIA effect of aberrant mesocorticolimbic functional coupling in adulthood. Furthermore, chronic intermittent treatment with low-dose THC during the peripubertal period caused an increase in sensitivity to amphetamine (indicative of aberrant mesolimbic dopamine transmission) in PolyIC-treated offspring compared to PBS-treated offspring, suggestive of a synergistic effect of these two environmental risk factors. In conclusion, the findings presented in this thesis have provided clear evidence of dose-specific detrimental effects of 'adolescent' THC exposure on behaviour and the functional neural systems that may underpin these deficits which impact on behaviour and neural systems into adulthood.Cannabis abuse can produce deficits in cognition and has been implicated as a 'late' environmental risk factor in the pathogenesis of the poly-factorial disorder schizophrenia. Evidence suggests an age-related susceptibility to the deleterious effects of cannabis as early onset of use may increase the vulnerability of the brain to the adverse consequences of cannabis abuse. Animal models are crucial for exploration of mechanistic and causative theories, and long-term behavioural consequences of adolescent cannabis abuse in a controlled experimental environment. This thesis evaluates the vulnerability of the adolescent/peripubertal brain to Δ9-tetrahydrocannabinol (THC), the principal psychoactive constituent of cannabis, and explores the potential interplay between this schizophrenia-related 'late' environmental risk factor and an 'early' environmental risk factor (prenatal infection - maternal immune activation (MIA)) on functional neural systems and behaviours relevant to schizophrenia. Cannabinoid CB1 receptor ontogeny (activated in the brain by the receptor ligand THC) within important cognitive substrates, the prefrontal cortex (PFC) and hippocampus, was investigated to delineate a period of neurodevelopmental vulnerability for peripubertal THC treatment. CB1 receptor ligand binding revealed that the PFC and hippocampus follow differential late maturational trajectories throughout the peripubertal period. The 'vulnerability window' for peripubertal THC treatment was defined as post-natal day (PD) 35-56 to encompass the dynamic peripubertal ontogenetic patterns of the CB1 receptor in both these regions. Furthermore, age-related alterations in cerebral metabolism and regional functional connectivity profiles were evident in the hippocampus and important neuromodulatory nuclei including the ventral tegmental area, dorsal raphe, locus coeruleus and the diagonal band of Broca.;Acute THC administration (5mg/kg) produced hypometabolism in the thalamus and an altered functional connectivity profile between thalamic nuclei and the PFC, hippocampus and the nucleus accumbens. THC-induced anomalistic neural activity was evident in key neuromodulatory nuclei and produced perturbed functional connectivity within acetylcholine, noradrenaline, and dopamine neural pathways. Acute THC treatment resulted in alterations in cerebral metabolism in the amygdala and aberrant functional connectivity profiles between amygdaloid nuclei and the hippocampus, PFC and nucleus accumbens. There appeared to be an age-related sensitivity to THC in several thalamic, neuromodulatory and amygdaloid nuclei. Peripubertal low-dose intermittent THC (3.5mg/kg, 3 times a week), mimetic of light, recreational adolescent cannabis use, produced long-term cognitive inflexibility, as measured by the attentional-set shifting task, perturbed cerebral metabolism in the dorsolateral orbital cortex and the nucleus accumbens core and altered functional coupling between both these regions and neural substrates subserving reward-related learning including prefrontal, septal and amygdala subfields. High-dose daily THC (7mg/kg) throughout the peripubertal period, mimetic of heavy daily cannabis abuse, did not precipitate any schizophrenia-related behaviours in adulthood. MIA induced by prenatal exposure to the immune-stimulating agent polyriboinosinic-polyribocytidilic acid (PolyIC) did not produce any schizophrenia-related phenotypes in adulthood. However, prenatal PolyIC exposure produced residual hypermetabolism within discrete components of the prefrontal cortex dorsolateral orbital and cingulate cortices and hypometabolism within the CA3 subfield of the hippocampus. The functional connectivity signatures of all these regions indicated a unified MIA effect of aberrant mesocorticolimbic functional coupling in adulthood. Furthermore, chronic intermittent treatment with low-dose THC during the peripubertal period caused an increase in sensitivity to amphetamine (indicative of aberrant mesolimbic dopamine transmission) in PolyIC-treated offspring compared to PBS-treated offspring, suggestive of a synergistic effect of these two environmental risk factors. In conclusion, the findings presented in this thesis have provided clear evidence of dose-specific detrimental effects of 'adolescent' THC exposure on behaviour and the functional neural systems that may underpin these deficits which impact on behaviour and neural systems into adulthood