In vitro characterisation of cell-level neurophysiological diversity in the rostral nucleus reuniens of adult mice

PublishedThis is the author accepted manuscript. The final version is available from Wiley via the DOI in this record.The nucleus reuniens (Re) is the largest of the midline thalamic nuclei. We have performed a detailed neurophysiological characterization of neurons in the rostral Re of brain slices prepared from adult male mice. At resting potential (−63.7 ± 0.6 mV), circa 90% of Re neurons fired action potentials, typically continuously at ∼8 Hz. Although Re neurons experience a significant spontaneous barrage of fast, amino-acid-mediate synaptic transmission, this was not predominantly responsible for spontaneous spiking as firing persisted in the presence of glutamate and GABA receptor antagonists. With resting potential preset to −80 mV −20 pA current injections revealed a mean input resistance of 615 MΩ and mean time constant of 38 ms. Following cessation of this stimulus a significant rebound potential was seen that was sometimes large enough to trigger a short burst of very high frequency (100–300 Hz) firing. In most cells short (2 ms), strong (2 nA) current injections elicited a single spike followed by a large afterdepolarizing potential (ADP) which, when suprathreshold, generated high frequency spiking. Similarly, in the majority of cells preset at −80 mV, 500 ms depolarizing current injections to cells led to a brief initial burst of very high frequency firing, although this was lost when cells were preset at −72 mV. Biophysical and pharmacological experiments indicate a prominent role for T-type Ca2+ channels in the high-frequency bursting of Re neurons. Finally, we describe a novel form of activity-dependent intrinsic plasticity that persistently eliminates the burst firing potential of Re neurons

Voltage- and Temperature-Dependent Allosteric Modulation of α7 Nicotinic Receptors by PNU120596

This is the final version of the article. Available from Frontiers Media via the DOI in this record.Alpha7 nicotinic acetylcholine receptors (α7 nAChR) are widely distributed throughout the central nervous system and are found at particularly high levels in the hippocampus and cortex. Several lines of evidence indicate that pharmacological enhancement of α7 nAChRs function could be a potential therapeutic route to alleviate disease-related cognitive deficits. A recent pharmacological approach adopted to increase α7 nAChR activity has been to identify selective positive allosteric modulators (PAMs). α7 nAChR PAMs have been divided into two classes: type I PAMs increase agonist potency with only subtle effects on kinetics, whereas type II agents produce additional dramatic effects on desensitization and deactivation kinetics. Here we report novel observations concerning the pharmacology of the canonical type II PAM, PNU120596. Using patch clamp analysis of acetylcholine (ACh)-mediated currents through recombinant rat α7 nAChR we show that positive allosteric modulation measured in two different ways is greatly attenuated when the temperature is raised to near physiological levels. Furthermore, PNU120596 largely removes the strong inward rectification usually exhibited by α7 nAChR-mediated responses

Disrupted in schizophrenia 1 and synaptic function in the mammalian central nervous system

This is the final version of the article. Available from the publisher via the DOI in this record.The disrupted in schizophrenia 1 (DISC1) gene is found at the breakpoint of an inherited chromosomal translocation, and segregates with major mental illnesses. Its potential role in central nervous system (CNS) malfunction has triggered intensive investigation of the biological roles played by DISC1, with the hope that this may shed new light on the pathobiology of psychiatric disease. Such work has ranged from investigations of animal behavior to detailed molecular-level analysis of the assemblies that DISC1 forms with other proteins. Here, we discuss the evidence for a role of DISC1 in synaptic function in the mammalian CNS.M. Kurihara was supported by a Medical Research Council Industrial collaborative studentship in collaboration with Pfizer, who also supported aspects of DISC1-related work in A. D. Randall’s laborator

Muscarinic receptor-dependent long term depression in the perirhinal cortex and recognition memory are impaired in the rTg4510 mouse model of tauopathy.

This is the final version of the article. Available from the publisher via the DOI in this record.Neurodegenerative diseases affecting cognitive dysfunction, such as Alzheimer's disease and fronto-temporal dementia, are often associated impairments in the visual recognition memory system. Recent evidence suggests that synaptic plasticity, in particular long term depression (LTD), in the perirhinal cortex (PRh) is a critical cellular mechanism underlying recognition memory. In this study, we have examined novel object recognition and PRh LTD in rTg4510 mice, which transgenically overexpress tauP301L. We found that 8-9 month old rTg4510 mice had significant deficits in long- but not short-term novel object recognition memory. Furthermore, we also established that PRh slices prepared from rTg4510 mice, unlike those prepared from wildtype littermates, could not support a muscarinic acetylcholine receptor-dependent form of LTD, induced by a 5 Hz stimulation protocol. In contrast, bath application of the muscarinic agonist carbachol induced a form of chemical LTD in both WT and rTg4510 slices. Finally, when rTg4510 slices were preincubated with the acetylcholinesterase inhibitor donepezil, the 5 Hz stimulation protocol was capable of inducing significant levels of LTD. These data suggest that dysfunctional cholinergic innervation of the PRh of rTg4510 mice, results in deficits in synaptic LTD which may contribute to aberrant recognition memory in this rodent model of tauopathy.SES was supported by a Medical Research Council studentship. JTB was an Alzheimer’s Research UK Senior Research Fellow. Eli Lilly & Co supplied the rTg4510 mice

Initiation and slow propagation of epileptiform activity from ventral to dorsal medial entorhinal cortex is constrained by an inhibitory gradient.

This is the author accepted manuscript. The final version is available from Wiley via the DOI in this record.The medial entorhinal cortex (mEC) has an important role in the generation and propagation of seizure activity. The organisation of the mEC is such that a number of dorso-ventral relationships exist in neurophysiological properties of neurons. These range from intrinsic and synaptic properties to density of inhibitory connectivity. We examined the influence of these gradients on generation and propagation of epileptiform activity in the mEC. Using a 16-shank silicon probe array to record along the dorso-ventral axis of the mEC in vitro, we found 4-aminopyridine (4-AP) application produces ictal-like activity originating predominantly in ventral areas. This activity spreads to dorsal mEC at a surprisingly slow velocity (138 μm.s-1), while cross-site interictal-like activity appeared relatively synchronous. We propose that ictal propagation is constrained by differential levels of GABAergic control since increasing (diazepam) or decreasing (Ro19-4603) GABAAreceptor activation, respectively, reduced or increased the slope of ictal initiation. The observation that ictal activity is predominately generated in ventral mEC was replicated using a separate 0-Mg2+model of epileptiform activity in vitro. By using a distinct disinhibition model (co-application of kainate and picrotoxin) we show that additional physiological features (for example intrinsic properties of mEC neurons) still produce a prevalence for interictal-like initiation in ventral mEC. These findings suggest that the ventral mEC is more likely to initiate hyperexcitable discharges than dorsal, and that seizure propagation is highly dependent on levels of GABAergic expression across the mEC. This article is protected by copyright. All rights reserved.This work was supported by a University of Exeter and Eli Lilly studentship (T.R). P.M 513 was supported by an MRC Proximity to Discovery award in partnership with 514 AstraZeneca. K.G.P was an employee of Eli Lilly. A.D.R was part funded by a Royal 515 Society Industrial Fellowship. J.T.B was an Alzheimer’s Research UK Senior Research 516 Fellow (ARUK-SRF2012-6)

Disrupted hippocampal sharp-wave ripple-associated spike dynamics in a transgenic mouse model of dementia.

This is the peer reviewed version of the article, which has been published in final form at DOI: 10.1113/jphysiol.2014.282889. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Self-Archiving.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. This article is protected by copyright. All rights reserved.Alzheimer’s Research UKMedical Research Counci

Neurophysiological alterations in the nucleus reuniens of a mouse model of Alzheimer's disease.

This is the author accepted manuscriptRecently, increased neuronal activity in nucleus reuniens (Re) has been linked to hyperexcitability within hippocampal-thalamo-cortical networks in the J20 mouse model of amyloidopathy. Here in vitro whole-cell patch clamp recordings were used to compare old pathology-bearing J20 mice and wild-type controls to examine whether altered intrinsic electrophysiological properties could contribute to the amyloidopathy-associated Re hyperactivity. A greater proportion of Re neurons display hyperpolarized membrane potentials in J20 mice without changes to the incidence or frequency of spontaneous action potentials. Re neurons recorded from J20 mice did not exhibit increased action potential generation in response to depolarizing current stimuli but an increased propensity to rebound burst following hyperpolarizing current stimuli. Increased rebound firing did not appear to result from alterations to T-type Ca2+ channels. Finally, in J20 mice, there was an ~8% reduction in spike width, similar to what has been reported in CA1 pyramidal neurons from multiple amyloidopathy mice. We conclude that alterations to the intrinsic properties of Re neurons may contribute to hippocampal-thalmo-cortical hyperexcitability observed under pathological beta-amyloid load.Alzheimer´s Research UKEli Lilly and Company Limited (T/A Lilly

Altered intrinsic pyramidal neuron properties and pathway-specific synaptic dysfunction underlie aberrant hippocampal network function in a mouse model of Tauopathy.

Final published version of article. This article is freely available online through the J Neurosci Author Open Choice option.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.Medical Research Council (MRC)Royal SocietyAlzheimer's Research United Kingdo

Impaired speed encoding and grid cell periodicity in a mouse model of tauopathy

This is the final version. Available on open access from eLife Sciences Publications via the DOI in this record. 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.Alzheimer’s Research U