The function of neural circuits and networks can be controlled, in part, by modulating the synchrony of their components' activities. Network hypersynchrony and altered oscillatory rhythmic activity ...may contribute to cognitive abnormalities in Alzheimer disease (AD). In this condition, network activities that support cognition are altered decades before clinical disease onset, and these alterations predict future pathology and brain atrophy. Although the precise causes and pathophysiological consequences of these network alterations remain to be defined, interneuron dysfunction and network abnormalities have emerged as potential mechanisms of cognitive dysfunction in AD and related disorders. Here, we explore the concept that modulating these mechanisms may help to improve brain function in these conditions.
Alzheimer's disease (AD) results in cognitive decline and altered network activity, but the mechanisms are unknown. We studied human amyloid precursor protein (hAPP) transgenic mice, which simulate ...key aspects of AD. Electroencephalographic recordings in hAPP mice revealed spontaneous epileptiform discharges, indicating network hypersynchrony, primarily during reduced gamma oscillatory activity. Because this oscillatory rhythm is generated by inhibitory parvalbumin (PV) cells, network dysfunction in hAPP mice might arise from impaired PV cells. Supporting this hypothesis, hAPP mice and AD patients had decreased levels of the interneuron-specific and PV cell-predominant voltage-gated sodium channel subunit Nav1.1. Restoring Nav1.1 levels in hAPP mice by Nav1.1-BAC expression increased inhibitory synaptic activity and gamma oscillations and reduced hypersynchrony, memory deficits, and premature mortality. We conclude that reduced Nav1.1 levels and PV cell dysfunction critically contribute to abnormalities in oscillatory rhythms, network synchrony, and memory in hAPP mice and possibly in AD.
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▸ Network hypersynchrony emerges during reduced gamma oscillatory activity in hAPP mice ▸ PV cells in hAPP mice have reduced Nav1.1 levels and impaired functions ▸ Memory deficits in hAPP mice are linked to aberrant network hypersynchrony ▸ Restoring Nav1.1 levels improves network activity and memory functions in hAPP mice
Depletion of a voltage-gated sodium channel in inhibitory interneurons is associated with abnormal patterns of neuronal activity and memory deficits in an hAPP mouse model of Alzheimer's disease (AD). Re-expression of this protein restores normal activity and oscillatory rhythms, ameliorating AD-associated memory deficits.
Alzheimer's disease is the most frequent neurodegenerative disorder and the most common cause of dementia in the elderly. Diverse lines of evidence suggest that amyloid-beta (Abeta) peptides have a ...causal role in its pathogenesis, but the underlying mechanisms remain uncertain. Here we discuss recent evidence that Abeta may be part of a mechanism controlling synaptic activity, acting as a positive regulator presynaptically and a negative regulator postsynaptically. The pathological accumulation of oligomeric Abeta assemblies depresses excitatory transmission at the synaptic level, but also triggers aberrant patterns of neuronal circuit activity and epileptiform discharges at the network level. Abeta-induced dysfunction of inhibitory interneurons likely increases synchrony among excitatory principal cells and contributes to the destabilization of neuronal networks. Strategies that block these Abeta effects may prevent cognitive decline in Alzheimer's disease. Potential obstacles and next steps toward this goal are discussed.
In light of the rising prevalence of Alzheimer’s disease (AD), new strategies to prevent, halt, and reverse this condition are needed urgently. Perturbations of brain network activity are observed in ...AD patients and in conditions that increase the risk of developing AD, suggesting that aberrant network activity might contribute to AD-related cognitive decline. Human amyloid precursor protein (hAPP) transgenic mice simulate key aspects of AD, including pathologically elevated levels of amyloid-β peptides in brain, aberrant neural network activity, remodeling of hippocampal circuits, synaptic deficits, and behavioral abnormalities. Whether these alterations are linked in a causal chain remains unknown. To explore whether hAPP/amyloid-β–induced aberrant network activity contributes to synaptic and cognitive deficits, we treated hAPP mice with different antiepileptic drugs. Among the drugs tested, only levetiracetam (LEV) effectively reduced abnormal spike activity detected by electroencephalography. Chronic treatment with LEV also reversed hippocampal remodeling, behavioral abnormalities, synaptic dysfunction, and deficits in learning and memory in hAPP mice. Our findings support the hypothesis that aberrant network activity contributes causally to synaptic and cognitive deficits in hAPP mice. LEV might also help ameliorate related abnormalities in people who have or are at risk for AD.
Patients with Alzheimer's disease or other neurodegenerative disorders show remarkable fluctuations in neurological functions, even during the same day. These fluctuations cannot be caused by sudden ...loss or gain of nerve cells. Instead, it is likely that they reflect variations in the activity of neural networks and, perhaps, chronic intoxication by abnormal proteins that the brain is temporarily able to overcome. These ideas have far-reaching therapeutic implications.
Inhibitory interneurons regulate the oscillatory rhythms and network synchrony that are required for cognitive functions and disrupted in Alzheimer’s disease (AD). Network dysrhythmias in AD and ...multiple neuropsychiatric disorders are associated with hypofunction of Nav1.1, a voltage-gated sodium channel subunit predominantly expressed in interneurons. We show that Nav1.1-overexpressing, but not wild-type, interneuron transplants derived from the embryonic medial ganglionic eminence (MGE) enhance behavior-dependent gamma oscillatory activity, reduce network hypersynchrony, and improve cognitive functions in human amyloid precursor protein (hAPP)-transgenic mice, which simulate key aspects of AD. Increased Nav1.1 levels accelerated action potential kinetics of transplanted fast-spiking and non-fast-spiking interneurons. Nav1.1-deficient interneuron transplants were sufficient to cause behavioral abnormalities in wild-type mice. We conclude that the efficacy of interneuron transplantation and the function of transplanted cells in an AD-relevant context depend on their Nav1.1 levels. Disease-specific molecular optimization of cell transplants may be required to ensure therapeutic benefits in different conditions.
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•Nav1.1-enhanced interneuron transplants reduce deficits in Alzheimer model•Nav1.1-deficient interneuron transplants cause behavioral deficits in wild-type mice•Nav1.1 elevation accelerates action potential kinetics in transplanted interneurons•Molecular optimization of cell transplants is required for therapeutic benefits
Inhibitory interneurons regulate brain rhythms and cognitive functions disrupted by Alzheimer’s disease (AD). Martinez-Losa et al. show that the level of the voltage-gated sodium channel subunit Nav1.1 in interneuron transplants regulates their therapeutic efficacy in an AD mouse model.
Striatal GABAergic microcircuits are critical for motor function, yet their properties remain enigmatic due to difficulties in targeting striatal interneurons for electrophysiological analysis. Here, ...we use Lhx6-GFP transgenic mice to identify GABAergic interneurons and investigate their regulation of striatal direct- and indirect-pathway medium spiny neurons (MSNs). We find that the two major interneuron populations, persistent low-threshold spiking (PLTS) and fast spiking (FS) interneurons, differ substantially in their excitatory inputs and inhibitory outputs. Excitatory synaptic currents recorded from PLTS interneurons are characterized by a small, nonrectifying AMPA receptor-mediated component and a NMDA receptor-mediated component. In contrast, glutamatergic synaptic currents in FS interneurons have a large, strongly rectifying AMPA receptor-mediated component, but no detectable NMDA receptor-mediated responses. Consistent with their axonal morphology, the output of individual PLTS interneurons is relatively weak and sparse, whereas FS interneurons are robustly connected to MSNs and other FS interneurons and appear to mediate the bulk of feedforward inhibition. Synaptic depression of FS outputs is relatively insensitive to firing frequency, and dynamic-clamp experiments reveal that these short-term dynamics enable feedforward inhibition to remain efficacious across a broad frequency range. Surprisingly, we find that FS interneurons preferentially target direct-pathway MSNs over indirect-pathway MSNs, suggesting a potential mechanism for rapid pathway-specific regulation of striatal output pathways.
Neural network dysfunction may play an important role in Alzheimer's disease (AD). Neuronal circuits vulnerable to AD are also affected in human amyloid precursor protein (hAPP) transgenic mice. hAPP ...mice with high levels of amyloid-β peptides in the brain develop AD-like abnormalities, including cognitive deficits and depletions of calcium-related proteins in the dentate gyrus, a region critically involved in learning and memory. Here, we report that hAPP mice have spontaneous nonconvulsive seizure activity in cortical and hippocampal networks, which is associated with GABAergic sprouting, enhanced synaptic inhibition, and synaptic plasticity deficits in the dentate gyrus. Many Aβ-induced neuronal alterations could be simulated in nontransgenic mice by excitotoxin challenge and prevented in hAPP mice by blocking overexcitation. Aberrant increases in network excitability and compensatory inhibitory mechanisms in the hippocampus may contribute to Aβ-induced neurological deficits in hAPP mice and, possibly, also in humans with AD.
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