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

Abstract

Key pointsr High frequency (100-250 Hz) neuronal oscillations in the hippocampus, known as sharp-wave ripples (SWRs), synchronise the firing behaviour of groups of neurons and play a key role in memory consolidation.r Learning and memory are severely compromised in dementias such as Alzheimer's disease; however, the effects of dementia-related pathology on SWRs are unknown.r The frequency and temporal structure of SWRs was disrupted in a transgenic mouse model of tauopathy (one of the major hallmarks of several dementias).r Excitatory pyramidal neurons were more likely to fire action potentials in a phase-locked manner during SWRs in the mouse model of tauopathy; conversely, inhibitory interneurons were less likely to fire phase-locked spikes during SWRs.r These findings indicate there is reduced inhibitory control of hippocampal network events and point to a novel mechanism which may underlie the cognitive impairments in this model of dementia.Abstract 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 probably 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-to 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 point to a novel mechanism which may contribute to impairments in memory consolidation in this model of dementia.

Sleep: A Novel Mechanistic Pathway, Biomarker, and Treatment Target in the Pathology of Alzheimer's Disease?

“…Tau within the MTL diminishes the expression of hippocampal ripples in rodents, resulting in less temporally synchronized ripple events 104 . This desynchrony is, in part, due to loss of GABA-dependent inhibition that dictates patterned neural firing and thus governs neural oscillations 104 .…”

“…This desynchrony is, in part, due to loss of GABA-dependent inhibition that dictates patterned neural firing and thus governs neural oscillations 104 . Tau is further associated with abnormally long hyperpolarized down states and impaired depolarizing up states during NREM slow oscillations within the cortex 105 .…”

Altered Intrinsic Pyramidal Neuron Properties and Pathway-Specific Synaptic Dysfunction Underlie Aberrant Hippocampal Network Function in a Mouse Model of Tauopathy

“…In vivo electrophysiological recordings. Methods were as described previously (Witton et al, 2014). Briefly, mice were implanted with custom microdrives containing four independently movable tetrodes.…”

“…Work in this model has revealed tauopathy-associated morphological and electrophysiological changes in rTg4510 cortical neurons, including dendritic and synaptic atrophy, depolarization of the resting potential, and increased "sag" potentials (Rocher et al, 2010;Crimins et al, 2011Crimins et al, , 2012. Furthermore, recent work has identified disturbances to hippocampal sharp wave-ripple oscillations (Witton et al, 2014) and spatial encoding in rTg4510 mice (Cheng and Ji, 2013), suggesting a level of hippocampal network dysfunction. Thus, it is apparent that tau-associated neuropathology induces changes in neuronal cellular and network physiology, likely leading to cognitive behavioral impairments in tasks dependent on these circuits.…”

Electrical and Network Neuronal Properties Are Preferentially Disrupted in Dorsal, But Not Ventral, Medial Entorhinal Cortex in a Mouse Model of Tauopathy

“…Evidence from optogenetically driven gamma oscillations in mEC slices suggests that the disruption in theta-gamma cross-frequency coupling might arise from impairment in excitatory drive onto fast-spiking interneurons (Pastoll et al, 2013). Indeed, we have recently reported that glutamatergic drive on to CA1 hippocampal interneurons is defective in rTg4510 mice (Witton et al, 2014), contributing to an emerging picture of the disruption of GABAergic circuits in mouse models of dementia (Driver et al, 2007;Palop et al, 2007;Baglietto-Vargas et al, 2010;Verret et al, 2012).…”