Astrocyte and Plasticity

Synaptic Plasticity

The roles of neurons in higher brain functions such as learning and memory have been well established. Hebb’s law of learning, developed by a Canadian psychologist Donald Hebb, reveals that the material basis of brain memory is synaptic plasticity. Initially, synaptic plasticity refers to the morphological and functional modifications of synaptic connections between neurons, which are mainly manifested in the forms of long term potentiation (LTP) and long term depression (LTD). When two neurons are connected and a nerve impulse occurs, the synaptic transmission between them is enhanced, resulting in more efficient neuronal activation. LTP is the primary form of synaptic plasticity, and both LTP and LTD serve as the biological basis for higher brain functions, such as learning and memory [1, 2].

Astrocyte and Synaptic Plasticity

After the discovery of various functions of neurons in higher brain activities, astrocytes have also been found to be closely related to higher functions of the brain. After Albert Einstein’s death in the 1950s, it was found that the only difference between his brain and that of a normal human was the greater number and size of astrocytes and their processes. Therefore, it was hypothesized that astrocytes must play significant roles in higher functions of the brain. Over the past two decades, there has been a significant advancement in astrocyte research. As the role of astrocytes in higher brain functions has become clearer, their involvement in synaptic plasticity has also been established. The definition of synaptic plasticity has also been extended and developed. Here, we summarize that astrocytes play a crucial role in synaptic plasticity mainly through a few aspects including calcium signaling, release of gliotransmitters, interactions with neurons, and astrocytic plasticity.

Calcium Signaling and the Release of Gliotransmitters

Earlier studies have demonstrated that calcium signaling in astrocytes regulates synaptic plasticity by inducing astrocytic glutamate release which causes an NMDA receptor-dependent increase in miniature postsynaptic currents (PSCs) frequency by acting on extrasynaptic NMDA receptors [3]. In 2004, it was reported that glutamate released from astrocytes could elicit AMPA receptor-mediated spontaneous excitatory PSCs on pyramidal neurons in the CA1 region, thereby regulating synaptic plasticity [4]. In addition, in vivo cholinergic activity evoked by sensory or electrical stimulation elevates the concentration of calcium ions in hippocampal astrocytes, which in turn induces LTP of hippocampal CA3-CA1 synapses by releasing glutamate [5].

In addition to glutamate, astrocytes also release other gliotransmitters after Ca²⁺ elevations, most prominently D-serine, the co-agonist of NMDA receptor [6, 7] and ATP [8]. It has been demonstrated that the release of D-serine from astrocytes controls NMDAR-dependent plasticity in neighboring excitatory synapses. Moreover, LTP of synaptic transmission also depends on the release of D-serine from astrocytes [6].

Furthermore, ATP released from astrocytes modulates depressive-like behavior in animal models and is very likely to adjust clinical depression in patients. Additionally, a decreased astrocytic release of ATP lead to less stimulation by P2X2Rs at GABAergic interneurons in the medial prefrontal cortex (mPFC), thus reducing GABAergic inhibition and elevating excitability [9]. Astrocytic ATP release is certainly important in astrocyte-neuron reciprocal communications.

Aside from the typical ones discussed above, lactate is also a crucial gliotransmitter especially to postsynaptic neurons. Through glycogenolysis, astrocytes convert glycogen into lactate and release it into the synapses via MCT1 or MCT4 transporters. Then neurons are able to take up them through their MCT2 transporters. Lactate is an additional metabolic energy form provided by astrocytes to facilitate neuronal growth and modulate synaptic plasticity [10].

Influence on Synaptic Transmission through Interactions with Neurons

Besides regulating neuronal activity via the release of gliotransmitters, astrocytes also perform their functions in synaptic transmission by interacting with neurons through their astrocytic receptors located on their extracellular surface. For example, it was pointed out that astrocytic regulation of synapses is mainly based on intracellular Ca²⁺-dependent processes as well as results from receptor activation, particularly group I metabotropic glutamatergic receptors (mGluRs). Among these, subtype 5 receptors (mGluR5) are the major ones sensing the synaptic release of glutamate at astrocytic processes [11], rather than the low-affinity and rapidly desensitizing AMPAR on neurons [12]. Following their activation through mGluR5 during basal synaptic transmission, astrocytes increase the transmission efficiency in CA1 pyramidal cells via presynaptic adenosine A_2A receptors activation, suggesting their direct involvement with neurons in regulation of synaptic transmission [11].

P2X and P2Y receptors are specific receptors that bind to ATP and were determined to be expressed on both of neuronal and astrocytic cell membranes [13]. P2YRs expressed in astrocytes are involved in maintaining neural functions and astrocyte-neuron communications [14]. Stimulation of P2Y1Rs attenuates astrocytic NMDAR currents in PFC, but activation of P2Y4Rs by ATP releases vesicular glutamate from astrocytes, so as to facilitate NMDAR currents [15]. What’s more, the activation of astrocytic P2X7R by ATP results in the release of other gliotransmitters including glutamate and gamma-aminobutyric acid (GABA), subsequently stimulating neighboring neurons and regulating neuronal functions [13, 16, 17].

Moreover, a family of transmembrane proteins called EphrinBs and Eph receptors expressed in the synapses used to be known to regulate synaptic transmission and plasticity [18]. In addition to their presence on CA1 hippocampal neurons, they were also determined to be expressed on hippocampal astrocytes and regulate D-serine synthesis and release [7]. In addition, it was found that astrocytes communicate with neurons through interaction between EphrinA3, a ligand of EphA4 that is found in astrocytes, and EphA4 to modulate LTP [19]. Meanwhile, glutamate transporter 1 (GLT-1/EAAT2) is responsible of regulating the concentration of extracellular glutamate during the late phase of LTP. The interaction between EphrinA3 and EphA4 is also known to be involved in decreasing levels of GLT-1 for proper synapsing to occur [10]. Apparently, the induction of postsynaptic neuronal LTP requires the participation of astrocytes. Figure 1 shows the integrative model proposed for the postsynaptic neuron-astrocyte communication during memory formation [10].

Additionally, astrocytes also perform functions in memory-disruptive effects of intoxication through their receptors. A typical example of astrocyte-neuron interactions is that cannabinoid exposure in vivo activates astrocytic type-1 cannabinoid receptor (CB₁R) to induce glutamate release, which further activates NMDAR, triggering AMPAR internalization at CA3-CA1 synapses. These events ultimately lead to the induction of LTD at these synapses, altering the function of hippocampal circuits that likely become unable to process spatial working memory (SWM) [20]. It is worth to mention, the key mechanism involved in this case was largely dependent on the function of astrocytic CB₁R rather than on neuronal CB₁R, revealing a novel mechanistic views of the critical astrocytic role in learning and memory processes [20].

Astrocytic Plasticity

Astrocytes themselves are malleable and also known to exhibit plasticity, particularly under activation [21]. In rodent neocortical synaptic structures, 30-60 % is tripartite structures formed between astrocytes and neurons. In the hippocampus and somatosensory cortex IV, 60-90 % of the spiny protrusions are enveloped by astrocyte processes. The potential of astrocytic plasticity to control breastfeeding by affecting synapse formation through cellular process migration is one of its recognized examples [22]. Furthermore, “Super Mice” created by chimerizing human astrocytes into the mouse brain have dramatically enhanced their synaptic plasticity, as well as their fast learning and memory abilities [23]. Therefore, astrocytic plasticity directly impacts synaptic plasticity.

In order to better understand different perspectives on astrocyte and its relationship with plasticity, we have summarized the plasticity-related molecules into three categories: astrocytic plasticity (Astroplasticity), astrocytic plasticity in tripartite structure (Perisynaptic Astroplasticity) and neuronal plasticity (Neuroplasticity) in Table 1.

Conclusion

Astrocyte plays a crucial role in accomplishing neural activities in the brain by regulating both synaptic and non-synaptic plasticity (astrocytic plasticity), as well as working together with neurons through signal exchange. Comprehensive studies of astrocytes and their roles in plasticity are still on-going, the upcoming results will provide us opportunities to better understand the mechanisms underlying higher brain functions from multiple perspectives.

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