Optogenetics: implications for Alzheimer’s disease research and therapy

Mirzayi, Parsa; Shobeiri, Parnian; Kalantari, Amirali; Perry, George; Rezaei, Nima

doi:10.1186/s13041-022-00905-y

Cited by 24 publications

(25 citation statements)

References 201 publications

(185 reference statements)

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“…Other therapeutic approaches that are being pursued include modulation and enhancement of oscillations ( Chan et al, 2021a ; Mirzayi et al, 2022 ). Deep brain stimulation, transcranial magnetic stimulation, and transcranial electrical stimulation are all being explored as ways of modulating activity in AD with some modest improvements seen with these methods ( Laxton et al, 2010 ; Yu et al, 2021 ).…”

Section: Discussion and Future Directionsmentioning

confidence: 99%

Alzheimer’s disease as a synaptopathy: Evidence for dysfunction of synapses during disease progression

Meftah

Gan

2023

Front. Synaptic Neurosci.

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The synapse has consistently been considered a vulnerable and critical target within Alzheimer’s disease, and synapse loss is, to date, one of the main biological correlates of cognitive decline within Alzheimer’s disease. This occurs prior to neuronal loss with ample evidence that synaptic dysfunction precedes this, in support of the idea that synaptic failure is a crucial stage within disease pathogenesis. The two main pathological hallmarks of Alzheimer’s disease, abnormal aggregates of amyloid or tau proteins, have had demonstrable effects on synaptic physiology in animal and cellular models of Alzheimer’s disease. There is also growing evidence that these two proteins may have a synergistic effect on neurophysiological dysfunction. Here, we review some of the main findings of synaptic alterations in Alzheimer’s disease, and what we know from Alzheimer’s disease animal and cellular models. First, we briefly summarize some of the human evidence to suggest that synapses are altered, including how this relates to network activity. Subsequently, animal and cellular models of Alzheimer’s disease are considered, highlighting mouse models of amyloid and tau pathology and the role these proteins may play in synaptic dysfunction, either in isolation or examining how the two pathologies may interact in dysfunction. This specifically focuses on neurophysiological function and dysfunction observed within these animal models, typically measured using electrophysiology or calcium imaging. Following synaptic dysfunction and loss, it would be impossible to imagine that this would not alter oscillatory activity within the brain. Therefore, this review also discusses how this may underpin some of the aberrant oscillatory patterns seen in animal models of Alzheimer’s disease and human patients. Finally, an overview of some key directions and considerations in the field of synaptic dysfunction in Alzheimer’s disease is covered. This includes current therapeutics that are targeted specifically at synaptic dysfunction, but also methods that modulate activity to rescue aberrant oscillatory patterns. Other important future avenues of note in this field include the role of non-neuronal cell types such as astrocytes and microglia, and mechanisms of dysfunction independent of amyloid and tau in Alzheimer’s disease. The synapse will certainly continue to be an important target within Alzheimer’s disease for the foreseeable future.

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Section: Discussion and Future Directionsmentioning

confidence: 99%

Alzheimer’s disease as a synaptopathy: Evidence for dysfunction of synapses during disease progression

Meftah

Gan

2023

Front. Synaptic Neurosci.

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“…Optogenetics rapidly has become a standard tool in neuroscience research as it permits cell-type-specific targeting and temporally precise activity modulation [ 20 ]; both features are desirable for a gain or loss of function experiments. In the past decade, the optogenetic approach has been increasingly applied in biomedical research and cognitive neuroscience [ 48 , 49 , 50 , 51 ]. The most commonly used methods to deliver functional opsin genes are viruses, in vivo electroporation, and the generation of transgenic animals.…”

Section: Discussionmentioning

confidence: 99%

Feasibility of Canine Adenovirus Type 2 (CAV2) Based Vector for the Locus Coeruleus Optogenetic Activation in Non-Transgenic Rats: Implications for Functional Studies

et al. 2022

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The locus coeruleus norepinephrine (LC-NE) system modulates many visceral and cognitive functions, while LC-NE dysfunction leads to neurological and neurodegenerative conditions such as sleep disorders, depression, ADHD, or Alzheimer’s disease. Innovative viral-vector and gene-engineering technology combined with the availability of cell-specific promoters enabled regional targeting and selective control over phenotypically specific populations of neurons. We transduced the LC-NE neurons in adult male rats by delivering the canine adenovirus type 2-based vector carrying the NE-specific promoter PRSx8 and a light-sensitive channelrhodopsin-2 receptor (ChR2) directly in the LC or retrogradely from the LC targets. The highest ChR2 expression level was achieved when the virus was delivered medially to the trigeminal pathway and ~100μm lateral to the LC. The injections close or directly in the LC compromised the tissue integrity and NE cell phenotype. Retrograde labeling was more optimal given the transduction of projection-selective subpopulations. Our results highlight a limited inference of ChR2 expression from representative cases to the entire population of targeted cells. The actual fraction of manipulated neurons appears most essential for an adequate interpretation of the study outcome. The actual fraction of manipulated neurons appears most essential for an adequate interpretation of the study outcome. Thus, besides the cell-type specificity and the transduction efficiency, the between-subject variability in the proportion of the remaining viral-transduced targeted cell population must be considered in any functional connectivity study.

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“…For example, it has been suggested that CFC may play a role in Parkinson’s disease as excessive PAC between beta and gamma bands has been observed in advanced-stage patients with movement deficits [ 64 , 88 ]. Abnormal theta–gamma CFC has been implicated in Alzheimer’s disease, as coupled band synchronization plays a critical role in memory functions [ 89 , 90 ]. Also, theta–phase gamma–amplitude coupling has been seen as a marker of Attention Deficit Hyperactivity disorder (ADHD) in children [ 91 ].…”

Section: Neural Oscillations In Cognition and Neurological Disordersmentioning

confidence: 99%

Neuromodulation of Neural Oscillations in Health and Disease

Weiss

Kann

Wang

2023

Biology

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Using EEG and local field potentials (LFPs) as an index of large-scale neural activities, research has been able to associate neural oscillations in different frequency bands with markers of cognitive functions, goal-directed behavior, and various neurological disorders. While this gives us a glimpse into how neurons communicate throughout the brain, the causality of these synchronized network activities remains poorly understood. Moreover, the effect of the major neuromodulatory systems (e.g., noradrenergic, cholinergic, and dopaminergic) on brain oscillations has drawn much attention. More recent studies have suggested that cross-frequency coupling (CFC) is heavily responsible for mediating network-wide communication across subcortical and cortical brain structures, implicating the importance of neurotransmitters in shaping coordinated actions. By bringing to light the role each neuromodulatory system plays in regulating brain-wide neural oscillations, we hope to paint a clearer picture of the pivotal role neural oscillations play in a variety of cognitive functions and neurological disorders, and how neuromodulation techniques can be optimized as a means of controlling neural network dynamics. The aim of this review is to showcase the important role that neuromodulatory systems play in large-scale neural network dynamics, informing future studies to pay close attention to their involvement in specific features of neural oscillations and associated behaviors.

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Optogenetics: implications for Alzheimer’s disease research and therapy

Cited by 24 publications

References 201 publications

Alzheimer’s disease as a synaptopathy: Evidence for dysfunction of synapses during disease progression

Alzheimer’s disease as a synaptopathy: Evidence for dysfunction of synapses during disease progression

Feasibility of Canine Adenovirus Type 2 (CAV2) Based Vector for the Locus Coeruleus Optogenetic Activation in Non-Transgenic Rats: Implications for Functional Studies

Neuromodulation of Neural Oscillations in Health and Disease

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