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+)
- Ca++ increases in astrocytes elicit the regulated release of gliotransmitters, e.g. glutamate, GABA, ATP and adenosine (purines), D-serine
What is the process of gliotransmission in the tripartite synapse?
- Astrocyte reacts to NTs with elevation of Ca2+
- Ca2+ increase -> regulated release of calcium-dependent gliotransmitters (e.g. Glu, GABA, ATP, D-serine)
=> Astrocytes control neuronal excitability and synaptic transmission through calcium-dependent 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 -> affects 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
- Astrocytes in culture (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
