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Astrocytes in Brain Signalling

Astrocytes: Basic “Classical” Properties

Astrocytes, also known as 'star-shaped cells,' are a type of glial cell in the brain. Glia includes oligodendrocytes, microglia, and astrocytes.

• Oligodendrocytes: Wrap myelin around multiple axons.

• Microglia

• Astrocytes: Ensheath the synapse and wrap around the blood vessel via astrocyte end-feet, forming an astrocyte syncytium.

Astrocyte Morphology

• Cell Body (Soma): Approximately 20 μm in size.

• Main Branches: Around 1-2 μm in diameter.

• Fine Processes ('Microdomain'): 50-200 nm in size.

• Endfeet: 1-2 μm.

Astrocytes receive input from other axon terminals and interact with neuron dendrites, including apical and basal dendritic trees, dendritic spines, soma, node of Ranvier, axon initial segment (AIS), axon, myelin sheath, and axon terminal.

Electrophysiological Properties

Maintaining Extracellular Balance

Astrocytes terminate neurotransmission by taking up extracellular neurotransmitters like GABA and Glutamate via transporters such as GAT1, GAT3 (GABA transporters) and EAAT (glutamate transporter).

Astrocytes also buffer extracellular potassium ions ($K^+$), maintaining ionic balance.

Astrocyte Gap Junctions and K+ Buffering

Astrocytes form a syncytium connected by gap junctions, which are composed of connexons (6 connexins). This allows for the passage of ions like $K^+$.

Astrocyte Signalling: The $Ca^{2+}$ Transient

The calcium transient is a temporary rise in intracellular free calcium concentration ($Ca^{2+}$). Unlike neurons that communicate via electrical impulses (action potentials in mV lasting milliseconds), astrocytes primarily use chemical signalling.

Astrocytic Calcium Oscillations

Astrocytes release ATP and other signalling molecules, triggering calcium responses in neighboring astrocytes, increasing intracellular calcium. This creates a wave-like pattern across the astrocytic syncytium, known as astrocytic calcium waves or oscillations. These waves are terminated by a negative feedback from IP3 receptors on the endoplasmic reticulum.

Mechanism of Astrocytic $Ca^{2+}$ Transients

Astrocytes express neurotransmitter receptors for:

• Glutamate

• ATP

• Acetylcholine

• Endocannabinoids (eCBs)

• GABA

• Dopamine

• Noradrenaline

These neurotransmitters can induce an increase in intracellular calcium ($Ca^{2+}$).

Phospholipase C (PLC)/Inositol 1,4,5-Trisphosphate (IP3) Pathway

Activation of G-protein-coupled receptors (GPCR) leads to PLC hydrolyzing phosphatidylinositol 4,5-bisphosphate ($PIP_2$) into diacylglycerol (DAG) and IP3. Glutamate, GABA, and ATP/Adenosine act as GPCR ligands. IP3 increase activates IP3 receptors (IP3R) on the endoplasmic reticulum (ER), causing $Ca^{2+}$ release from the ER.

Unlike neurons, astrocytic $Ca^{2+}$ transients aren't due to voltage-gated $Ca^{2+}$ channels.

Synaptic Activation

Synaptic activation of astrocytes is pathway-specific, demonstrated by differences in calcium responses in the somata of astrocytes in the sensory afferent (SEN) cortex (CT) and thalamus.

Astrocytic Control of Brain Vasculature

Astrocytes connect neurons to blood vessels and mediate communication between them.

Mechanism of Astrocytic Control of Brain Vascular Tone

1. Sensing Neuronal Activity

2. Calcium Transients

3. Increase of Phospholipase A2 (PLA2) and Arachidonic Acid (AA): PLA2 produces AA.

4. Release of Substances: AA is converted into vasoactive substances like prostaglandin E2 (PGE2), hydroxyeicosatetraenoic acid (HETE), and epoxyeicosatrienoic acid (EET).

The vasomotor response to astrocyte-derived vasoactive agents depends on the resting state of cerebral arterioles. Vasodilating agents (e.g., PGE2) and vasoconstrictive agents (e.g., 20-HETE) are released by astrocytes.

BOLD Signals

Blood oxygenation level-dependent (BOLD) signals are related to brain activity, such as auditory, motor, language, and visual activation.

Tripartite Synapse: Physiological Consequences

The tripartite synapse involves neuron-to-astrocyte signalling and astrocyte-to-neuron signalling, in addition to the regular neuronal synaptic transmission, all occurring in proximity to a blood vessel.

Mechanism of Astrocyte-to-Neuron Signalling

Astrocytes release gliotransmitters that can influence neuronal activity, resulting in:

• Slow Outward Current (SOC): GABA acting on GABA-A receptors.

• Slow Inward Current (SIC).

Neurotransmitters vs. Gliotransmitters

Tripartite Synapse Components

Includes the presynaptic terminal, postsynaptic terminal (dendritic spine), and the astrocyte processes.

Roles of Astrocytes in Brain Function

• Astrocytes gate long-term depression at cortico-striatal synapses.

• Astrocytes modulate sensory-evoked neuronal gamma waves.

• Astrocytes (via their cannabinoid receptors-1) determine synaptic D-serine availability to enable recognition memory.

• Synapse-specific astrocyte gating of amygdala-related behavior.

• Astrocytes potentiate transmitter release at single hippocampal synapses and contribute to long-term potentiation.

• An excitatory loop with astrocytes contributes to drive neurons to epileptic seizure threshold.

• Enhanced astrocytic $Ca^{2+}$ signals contribute to neuronal excitotoxicity after status epilepticus.

• Neuronal synchrony mediated by astrocytic glutamate through activation of extrasynaptic NMDA receptors.

• Astrocytic modulation of sleep homeostasis and cognitive consequences of sleep loss.

Long-Term Potentiation (LTP)

Long-term potentiation involves high-frequency stimulation, leading to an increase in EPSP amplitude over time.

Astrocytes Contribute to Long-Term Potentiation

Astrocytes contribute to long-term potentiation at the CA3-CA1 synapse.

Astrocytes Gate Amygdala-Dependent Behavior

Designer receptors exclusively activated by designer drugs (DREADD) are used to activate or silence neurons with chemical agents like clozapine N-oxide (CNO). Astrocytic activation can increase IPSC frequency.

Old View vs. Current Understanding