Journal articles
Randall A, Jackson J, Witton J, Johnson J, Ahmed Z, Ward M, Hutton ML, Isaac JT, O'Neill MJ, Ashby MC, et al (In Press). Altered synapse stability in the early stages of tauopathy. Cell Reports-D-16-02088R2
Brady ES, Griffiths J, Andrianova L, Bielska MH, Saito T, Saido TC, Randall AD, Tamagnini F, Witton J, Craig MT, et al (2023). Alterations to parvalbumin-expressing interneuron function and associated network oscillations in the hippocampal - medial prefrontal cortex circuit during natural sleep in AppNL-G-F/NL-G-F mice.
Neurobiol Dis,
182Abstract:
Alterations to parvalbumin-expressing interneuron function and associated network oscillations in the hippocampal - medial prefrontal cortex circuit during natural sleep in AppNL-G-F/NL-G-F mice.
In the early stages of Alzheimer's disease (AD), the accumulation of the peptide amyloid-β (Aβ) damages synapses and disrupts neuronal activity, leading to the disruption of neuronal oscillations associated with cognition. This is thought to be largely due to impairments in CNS synaptic inhibition, particularly via parvalbumin (PV)-expressing interneurons that are essential for generating several key oscillations. Research in this field has largely been conducted in mouse models that over-express humanised, mutated forms of AD-associated genes that produce exaggerated pathology. This has prompted the development and use of knock-in mouse lines that express these genes at an endogenous level, such as the AppNL-G-F/NL-G-F mouse model used in the present study. These mice appear to model the early stages of Aβ-induced network impairments, yet an in-depth characterisation of these impairments in currently lacking. Therefore, using 16 month-old AppNL-G-F/NL-G-F mice, we analysed neuronal oscillations found in the hippocampus and medial prefrontal cortex (mPFC) during awake behaviour, rapid eye movement (REM) and non-REM (NREM) sleep to assess the extent of network dysfunction. No alterations to gamma oscillations were found to occur in the hippocampus or mPFC during either awake behaviour, REM or NREM sleep. However, during NREM sleep an increase in the power of mPFC spindles and decrease in the power of hippocampal sharp-wave ripples was identified. The latter was accompanied by an increase in the synchronisation of PV-expressing interneuron activity, as measured using two-photon Ca2+ imaging, as well as a decrease in PV-expressing interneuron density. Furthermore, although changes were detected in local network function of mPFC and hippocampus, long-range communication between these regions appeared intact. Altogether, our results suggest that these NREM sleep-specific impairments represent the early stages of circuit breakdown in response to amyloidopathy.
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Witton J, Brady ES, Craig MT (2023). Sleep-based neuronal oscillations as a physiological biomarker for Alzheimer's disease: is night time the right time?. Neural Regeneration Research, 19(7), 1417-1418.
Craig MT, Witton J (2022). A cellular switchboard in memory circuits.
Science,
377(6603), 262-263.
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A cellular switchboard in memory circuits.
Neurogliaform cells can direct the flow of information through the hippocampus.
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Walsh C, Ridler T, Margetts-Smith G, Garcia Garrido M, Witton J, Randall AD, Brown JT (2022). β Bursting in the Retrosplenial Cortex is a Neurophysiological Correlate of Environmental Novelty Which is Disrupted in a Mouse Model of Alzheimer's Disease. The Journal of Neuroscience, 42(37), 7094-7109.
Walsh C, Ridler T, Garrido MG, Witton J, Randall AD, Brown JT (2021). Beta bursting in the retrosplenial cortex is a neurophysiological correlate of environmental novelty which is disrupted in a mouse model of Alzheimer’s disease.
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Beta bursting in the retrosplenial cortex is a neurophysiological correlate of environmental novelty which is disrupted in a mouse model of Alzheimer’s disease
AbstractThe retrosplenial cortex (RSC) plays a significant role in spatial learning and memory, and is functionally disrupted in the early stages of Alzheimer’s disease. In order to investigate neurophysiological correlates of spatial learning and memory in this region we employed in vivo electrophysiology in awake, behaving mice, comparing neural activity between wild-type and J20 mice, a mouse model of Alzheimer’s disease-associated amyloidopathy. To determine the response of the RSC to environmental novelty local field potentials were recorded while mice explored novel and familiar recording arenas. In familiar environments we detected short, phasic bursts of beta (20-30 Hz) oscillations (beta bursts) which arose at a low but steady rate. Exposure to a novel environment rapidly initiated a dramatic increase in the rate, size and duration of beta bursts. Additionally, theta-beta cross-frequency coupling was significantly higher during novelty, and spiking of neurons in the RSC was significantly enhanced during beta bursts. Finally, aberrant beta bursting was seen in J20 mice, including increased beta bursting during novelty and familiarity, yet a loss of coupling between beta bursts and spiking activity. These findings, support the concept that beta bursting may be responsible for the activation and reactivation of neuronal ensembles underpinning the formation and maintenance of cortical representations, and that disruptions to this activity in J20 mice may underlie cognitive impairments seen in these animals.
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Meftah S, Witton J, Cavallini A, Murray TK, Jankowski L, Bose S, Ashby M, Brown JT (2020). Identifying early markers of synaptic dysfunction in a mouse model of tauopathy. Alzheimer's & Dementia, 16(S3).
Ridler T, Witton J, Phillips KG, Randall AD, Brown JT (2020). Impaired speed encoding and grid cell periodicity in a mouse model of tauopathy.
eLife,
9Abstract:
Impaired speed encoding and grid cell periodicity in a mouse model of tauopathy
Dementia is associated with severe spatial memory deficits which arise from dysfunction in hippocampal and parahippocampal circuits. For spatially sensitive neurons, such as grid cells, to faithfully represent the environment these circuits require precise encoding of direction and velocity information. Here, we have probed the firing rate coding properties of neurons in medial entorhinal cortex (MEC) in a mouse model of tauopathy. We find that grid cell firing patterns are largely absent in rTg4510 mice, while head-direction tuning remains largely intact. Conversely, neural representation of running speed information was significantly disturbed, with smaller proportions of MEC cells having firing rates correlated with locomotion in rTg4510 mice. Additionally, the power of local field potential oscillations in the theta and gamma frequency bands, which in wild-type mice are tightly linked to running speed, was invariant in rTg4510 mice during locomotion. These deficits in locomotor speed encoding likely severely impact path integration systems in dementia.
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Ridler T, Witton J, Phillips KG, Randall AD, Brown JT (2019). Impaired speed encoding is associated with reduced grid cell periodicity in a mouse model of tauopathy.
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Impaired speed encoding is associated with reduced grid cell periodicity in a mouse model of tauopathy
AbstractDementia is associated with severe spatial memory deficits which arise from dysfunction in hippocampal and parahippocampal circuits. For spatially-sensitive neurons, such as grid cells, to faithfully represent the environment these circuits require precise encoding of direction and velocity information. Here we have probed the firing rate coding properties of neurons in medial entorhinal cortex (MEC) in a mouse model of tauopathy. We find that grid cell firing patterns are largely absent in rTg4510 mice, while head direction tuning remains largely intact. Conversely, neural representation of running speed information was significantly disturbed, with smaller proportions of MEC cells having firing rates correlated with locomotion in rTg4510 mice. Additionally, the power of local field potential oscillations in the theta and gamma frequency bands, which in wildtype mice are tightly linked to running speed, was invariant in rTg4510 mice. These deficits in locomotor speed encoding likely severely impact path integration systems in dementia.
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Booth CA, Witton J, Nowacki J, Tsaneva-Atanasova K, Jones MW, Randall AD, Brown JT (2016). Altered Intrinsic Pyramidal Neuron Properties and Pathway-Specific Synaptic Dysfunction Underlie Aberrant Hippocampal Network Function in a Mouse Model of Tauopathy.
J Neurosci,
36(2), 350-363.
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Altered Intrinsic Pyramidal Neuron Properties and Pathway-Specific Synaptic Dysfunction Underlie Aberrant Hippocampal Network Function in a Mouse Model of Tauopathy.
UNLABELLED: the formation and deposition of tau protein aggregates is proposed to contribute to cognitive impairments in dementia by disrupting neuronal function in brain regions, including the hippocampus. We used a battery of in vivo and in vitro electrophysiological recordings in the rTg4510 transgenic mouse model, which overexpresses a mutant form of human tau protein, to investigate the effects of tau pathology on hippocampal neuronal function in area CA1 of 7- to 8-month-old mice, an age point at which rTg4510 animals exhibit advanced tau pathology and progressive neurodegeneration. In vitro recordings revealed shifted theta-frequency resonance properties of CA1 pyramidal neurons, deficits in synaptic transmission at Schaffer collateral synapses, and blunted plasticity and imbalanced inhibition at temporoammonic synapses. These changes were associated with aberrant CA1 network oscillations, pyramidal neuron bursting, and spatial information coding in vivo. Our findings relate tauopathy-associated changes in cellular neurophysiology to altered behavior-dependent network function. SIGNIFICANCE STATEMENT: Dementia is characterized by the loss of learning and memory ability. The deposition of tau protein aggregates in the brain is a pathological hallmark of dementia; and the hippocampus, a brain structure known to be critical in processing learning and memory, is one of the first and most heavily affected regions. Our results show that, in area CA1 of hippocampus, a region involved in spatial learning and memory, tau pathology is associated with specific disturbances in synaptic, cellular, and network-level function, culminating in the aberrant encoding of spatial information and spatial memory impairment. These studies identify several novel ways in which hippocampal information processing may be disrupted in dementia, which may provide targets for future therapeutic intervention.
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Witton J, Staniaszek L, Bartsch U, Randall AD, Jones MW, Brown JT (2015). Disrupted hippocampal sharp-wave ripple-associated spike dynamics in a transgenic mouse model of dementia.
Journal of Physiology,
In pressAbstract:
Disrupted hippocampal sharp-wave ripple-associated spike dynamics in a transgenic mouse model of dementia
Neurons within the CA1 region of the hippocampus are co-activated during high frequency (100-250 Hz) sharp wave ripple (SWR) activity in a manner that likely drives synaptic plasticity and promotes memory consolidation. In this study we have used a transgenic mouse model of dementia (rTg4510 mice) which overexpresses a mutant form of tau protein, to examine the effects of tauopathy on hippocampal SWRs and associated neuronal firing. Tetrodes were used to record simultaneous extracellular action potentials and local field potentials from the dorsal CA1 pyramidal cell layer of 7-8 month old wild-type and rTg4510 mice at rest in their home cage. At this age point these mice exhibit neurofibrillary tangles, neurodegeneration and cognitive deficits. Epochs of sleep or quiet restfulness were characterised by minimal locomotor activity and a low theta/delta ratio in the local field potential power spectrum. SWRs detected off-line were significantly lower in amplitude and had an altered temporal structure in rTg4510 mice. Nevertheless, the average frequency profile and duration of the SWRs were relatively unaltered. Putative interneurons displayed significantly less temporal and phase locking to SWRs in rTg4510 mice, whilst putative pyramidal neurons showed increased temporal and phase locking to SWRs. These findings indicate there is reduced inhibitory control of hippocampal network events and points to a novel mechanism which may contribute to impairments in memory consolidation in this model of dementia.
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Witton J, Padmashri R, Zinyuk LE, Popov VI, Kraev I, Line SJ, Jensen TP, Tedoldi A, Cummings DM, Tybulewicz VLJ, et al (2015). Hippocampal circuit dysfunction in the Tc1 mouse model of Down syndrome.
Nat Neurosci,
18(9), 1291-1298.
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Hippocampal circuit dysfunction in the Tc1 mouse model of Down syndrome.
Hippocampal pathology is likely to contribute to cognitive disability in Down syndrome, yet the neural network basis of this pathology and its contributions to different facets of cognitive impairment remain unclear. Here we report dysfunctional connectivity between dentate gyrus and CA3 networks in the transchromosomic Tc1 mouse model of Down syndrome, demonstrating that ultrastructural abnormalities and impaired short-term plasticity at dentate gyrus-CA3 excitatory synapses culminate in impaired coding of new spatial information in CA3 and CA1 and disrupted behavior in vivo. These results highlight the vulnerability of dentate gyrus-CA3 networks to aberrant human chromosome 21 gene expression and delineate hippocampal circuit abnormalities likely to contribute to distinct cognitive phenotypes in Down syndrome.
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Rodríguez JJ, Noristani HN, Hilditch T, Olabarria M, Yeh CY, Witton J, Verkhratsky A (2013). Increased densities of resting and activated microglia in the dentate gyrus follow senile plaque formation in the CA1 subfield of the hippocampus in the triple transgenic model of Alzheimer's disease.
Neurosci Lett,
552, 129-134.
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Increased densities of resting and activated microglia in the dentate gyrus follow senile plaque formation in the CA1 subfield of the hippocampus in the triple transgenic model of Alzheimer's disease.
Alzheimer's disease (AD) is an irreversible neurodegenerative disease that is characterised by the presence of β-amyloid (Aβ) plaques, neurofibrillary tangles (NFTs) and synaptic loss specifically in brain regions involved in learning and memory such as the neocortex and the hippocampus. Aβ depositions in the form of neuritic plaques trigger activation of microglia that is believed to be a common neuropathological feature of AD brains. As an integral part of the hippocampus, the dentate gyrus (DG) plays an important role in cognitive function. Although post-mortem studies suggest later involvement of the DG into the AD progression, changes in microglia have not been studied in this subfield of the hippocampus. In the present study the numerical density (Nv, #/mm(3)) of both resting (identified by tomato lectin staining) and activated (identified by Mac-1 immunoreactivity) microglia was analysed in the molecular layer (ML) of the DG in the triple transgenic (3xTg-AD) mouse model of AD at different ages (9, 12 and 18 months). The 3xTg-AD mouse model of AD showed a significant increase in the Nv of resting (by 75%) and activated (by 67%) at 18 months of age compared to non-Tg controls. These results indicate a complex microglial remodelling during AD progression.
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Forsyth LH, Witton J, Brown JT, Randall AD, Jones MW (2012). In Vitro and in Vivo Recording of Local Field Potential Oscillations in Mouse Hippocampus.
Curr Protoc Mouse Biol,
2(3), 273-294.
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In Vitro and in Vivo Recording of Local Field Potential Oscillations in Mouse Hippocampus.
Oscillations in hippocampal local field potentials (LFP) reflect the coordinated, rhythmic activity of constituent interneuronal and principal cell populations. Quantifying changes in oscillatory patterns and power therefore provides a powerful metric through which to infer mechanisms and functions of hippocampal network activity at the mesoscopic level, bridging single-neuron studies to behavioral assays of hippocampal function. Here, complementary protocols that enable mechanistic analyses of oscillation generation in vitro (in slices and a whole hippocampal preparation) and functional analyses of hippocampal circuits in behaving mice are described. Used together, these protocols provide a comprehensive view of hippocampal phenotypes in mouse models, highlighting oscillatory biomarkers of hippocampal function and dysfunction. Curr. Protoc. Mouse Biol. 2:273-294 © 2012 by John Wiley & Sons, Inc.
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Witton J, Brown JT, Jones MW, Randall AD (2010). Altered synaptic plasticity in the mossy fibre pathway of transgenic mice expressing mutant amyloid precursor protein.
Mol Brain,
3Abstract:
Altered synaptic plasticity in the mossy fibre pathway of transgenic mice expressing mutant amyloid precursor protein.
Aβ peptides derived from the cleavage of amyloid precursor protein are widely believed to play an important role in the pathophysiology of Alzheimer's disease. A common way to study the impact of these molecules on CNS function is to compare the physiology of transgenic mice that overproduce Aβ with non-transgenic animals. In the hippocampus, this approach has been frequently applied to the investigation of synaptic transmission and plasticity in the perforant and Schaffer collateral commissural pathways, the first and third components of the classical hippocampal trisynaptic circuit, respectively. Similar studies however have not been carried out on the remaining component of the trisynaptic circuit, the mossy fibre pathway. Using transverse hippocampal slices prepared from ~2 year old animals we have compared mossy fibre synaptic function in wild-type mice and their Tg2576 littermates which age-dependently overproduce Aβ. Input-output curves were not altered in slices from Tg2576 mice, but these animals exhibited a significant loss of the prominent frequency-facilitation expressed by the mossy fibre pathway. In addition to this change in short term synaptic plasticity, high frequency stimulation-induced, NMDA-receptor-independent LTP was absent in slices from the transgenic mice. These data represent the first description of functional deficits in the mossy fibre pathway of Aβ-overproducing transgenic mice.
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Rodríguez JJ, Witton J, Olabarria M, Noristani HN, Verkhratsky A (2010). Increase in the density of resting microglia precedes neuritic plaque formation and microglial activation in a transgenic model of Alzheimer's disease.
Cell Death Dis,
1(1).
Abstract:
Increase in the density of resting microglia precedes neuritic plaque formation and microglial activation in a transgenic model of Alzheimer's disease.
The formation of cerebral senile plaques composed of amyloid β peptide (Aβ) is a fundamental feature of Alzheimer's disease (AD). Glial cells and more specifically microglia become reactive in the presence of Aβ. In a triple transgenic model of AD (3 × Tg-AD), we found a significant increase in activated microglia at 12 (by 111%) and 18 (by 88%) months of age when compared with non-transgenic (non-Tg) controls. This microglial activation correlated with Aβ plaque formation, and the activation in microglia was closely associated with Aβ plaques and smaller Aβ deposits. We also found a significant increase in the area density of resting microglia in 3 × Tg-AD animals both at plaque-free stage (at 9 months by 105%) and after the development of a plaques (at 12 months by 54% and at 18 months by 131%). Our results show for the first time that the increase in the density of resting microglia precedes both plaque formation and activation of microglia by extracellular Aβ accumulation. We suggest that AD pathology triggers a complex microglial reaction: at the initial stages of the disease the number of resting microglia increases, as if in preparation for the ensuing activation in an attempt to fight the extracellular Aβ load that is characteristic of the terminal stages of the disease.
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Randall AD, Witton J, Booth C, Hynes-Allen A, Brown JT (2010). The functional neurophysiology of the amyloid precursor protein (APP) processing pathway.
Neuropharmacology,
59(4-5), 243-267.
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The functional neurophysiology of the amyloid precursor protein (APP) processing pathway.
Amyloid beta (Abeta) peptides derived from proteolytic cleavage of amyloid precursor protein (APP) are thought to be a pivotal toxic species in the pathogenesis of Alzheimer's disease (AD). Furthermore, evidence has been accumulating that components of APP processing pathway are involved in non-pathological normal function of the CNS. In this review we aim to cover the extensive body of research aimed at understanding how components of this pathway contribute to neurophysiological function of the CNS in health and disease. We briefly outline changes to clinical neurophysiology seen in AD patients before discussing functional changes in mouse models of AD which range from changes to basal synaptic transmission and synaptic plasticity through to abnormal synchronous network activity. We then describe the various neurophysiological actions that are produced by application of exogenous Abeta in various forms, and finally discuss a number or other neurophysiological aspects of the APP pathway, including functional activities of components of secretase complexes other than Abeta production.
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