Neuron-glial interactions and mental health Flashcards
Do glial cells affect behaviour?
Yes
e. g. Mice with human astrocytes
- perform better at cognitive tasks
- show enhanced long term potentiation (LTP) of synapses
What are the 3 ways astrocytes can affect behaviour?
- Homeostatic role
- Ability to release NTs -> gliotransmission
- Formation of astrocytic networks
What are the components of the tripartite synapse?
> Pre-synaptic neuron: releases NTs
Post-synaptic neuron
Astrocyte: reacts to NTs with elevation of Ca++ (<=> Ca2+)
What is the process of gliotransmission in the tripartite synapse?
> Astrocyte reacts to NTs with elevation of Ca2+
Ca2+ increase -> regulated release of calcium-dependant gliotransmitters (e.g. Glu, GABA, ATP, D-serine)
=> Astrocytes control neuronal excitability and synaptic transmission through calcium-dependant gliotransmitters
What are the 2 possible consequences of gliotransmission, supported by evidence?
Role in memory and sleep regulation
What is the evidence for a role of astrocytes in memory?
Han et al. (2012): Mice model mutated: lacking type 1 cannabinoid receptor (CB1R) in astroglial cells vs. Glu neurons vs. GABA neurons:
- Spatial working memory impaired in mice lacking CB1R on Glu or GABA neurons ; BUT preserved in mice lacking CB1R on astroglial cells
- Long term depression (LTD) impaired in mice lacking CB1R on Glu or GABA neurons ; BUT preserved in mice lacking CB1R on astroglial cells
Explanation: cannabinoid exposure in vivo sequentially activated astroglial CB1R
- astrocytes release Glu
- Glu binds to NMDA receptors
- AMPA receptor is internalised
- LTD is induced
- > mouse is lost (spatial working memory impaired)
=> Astrocytes can play an active role in cognition, and a role in its impairment in pathological states
What is the evidence for the role of astrocytes in sleep regulation?
> Adenosine plays a role in sleep homeostasis
Studies show adenosine comes from astrocytes
Astrocytes release gliotransmitters like ATP, which is converted extracellularly into adenosine
This exocytotic release is dependent of the SNARE protein
Genetic modification can abolish this SNARE-dependent release of gliotransmitters
- in mice: prevents both tonic and activity dependent extracellular accumulation of adenosine, which acts on A1 receptor
-> role of gliotransmitters (here ATP) in sleep regulation
-> Astrocytes modulate behaviour ; A1R role in regulation of sleep homeostasis
> Cognitive decline associated with sleep loss
What is the evidence that gap junctions interconnect astrocytes into networks?
> Astrocyte-astrocyte communication via gap junctions which allow passage of ions -> direct inter-cellular communication
Astrocytic gap junctions are made by 2 proteins: connexin-30 and connexin-43
Study of the coupling of astrocytes into networks by injecting fluorescent dye (e.g. biocytin) in astrocytes
-> gap junctions show selective permeability which can be regulated
> Permeability is age and region-specific
Transgenic animals that had both connexin-30 and connexin-43 knocked out, are unable to form gap junctions
How are astrocytic networks formed and affect neuronal activity?
Example with Glutamatergic synapses
- Release of NT from pre-synaptic Glu neuron
- NT interacts with receptors on astrocytes -> Ca2+ increase
- Gliotransmitters are released in astrocytes undergoing Ca2+ increase -> influence neuronal activity
- Glu and its derivative glutamine diffuse through astrocyte gap junctions
- > rise in Ca2+ spreads to neighbouring astrocytes = ‘calcium wave’ - Release of gliotransmitters at a remote synapse
- > affect the activity of underlying neuronal networks
What can astrocytic networks do?
> Regulate the generation of a rhythmic firing pattern in neurons, necessary for vital functions such as respiration and mastication
> Act as a hub for integrating signals from different brain areas
- Pereira and Furlan (2010): astrocytic networks are essential for voluntary behaviour ; only automatic behaviour could be executed purely by neuronal network
What are the 3 main lines of evidence on astrocytes and depression?
> Human studies: mainly post-mortem
Animal studies, including genetically modified animals
In vitro studies
What are the proposed neurophysiological processes underlying a depressed state?
> Monoamine hypothesis
Dysfunction of HPA axis, involved in the response to stress, may be implicated in the pathophysiology of depression
Circadian rhythm abnormalities: disruption of sleep patterns
Neurodegenerative and neuroinflammation alteration may be contributing factors, especially in late onset depression
What are the current statistics on pharmacological treatments efficacy?
> Between 30 and 50% of people with depression will not respond to anti depression medication
About 50% of sufferers are poor responders to pharmacotherapy in general
What is the evidence from animal studies on astrocytes’ role in depression?
> Astrocyte pathology is present in animal models of depression
Treatments that revert astrocyte pathology also revert symptoms of depression in animal models
What does the study on chronic unpredictable stress (CUS) on an animal model of depression show?
> Animals are subjected to a sequence of 2 stressors per day over an extended time period
Authors measured level of mRNA for a specific marker of astrocytes: glial fibrillary associated protein (GFAP)
- > Significant decrease of mRNA levels seen for the glial-specific marker GFAP
- > Effect of stress can be reversed by the glutamate-modulating drug Riluzole
> CUS affects animal behaviour in the sucrose preference test, leading to anhedonia (reduced preference for sucrose solution)
- reversed by Riluzole, in parallel with reduction observed in glial pathology
