Symmetric And Asymmetric Synapses Driving Neurodegenerative Disorders Part 1

Abstract: 

In 1959, E. G. Gray described two different types of synapses in the brain for the first time: symmetric and asymmetric. Later on, symmetric synapses were associated with inhibitory terminals, and asymmetric synapses to excitatory signaling. 

Symmetrical synapses are a form of connection between neurons and one of the key structures for transmitting information between neurons. According to the latest research, symmetrical synapses play a very important role in maintaining and improving memory in the brain.

Symmetrical synapses are plastic structures that can be changed and adjusted through various forms of learning and experience. Therefore, for improving memory and learning ability, through continuous learning and training, the establishment and development of symmetrical synapses in the brain can be promoted, thereby improving the efficiency and speed of information transmission between neurons.

In addition, studies have shown that the number and quality of symmetrical synapses are closely related to healthy brain function and cognitive ability. The development and repair of symmetrical synapses in the brain can be promoted by maintaining adequate sleep and proper nutrition. Therefore, establishing a healthy lifestyle and eating habits, as well as maintaining a good mentality and emotional state, plays a vital role in maintaining and improving memory and learning ability.

In future research, we can expect more discoveries, and through in-depth understanding and exploration of symmetrical synapses, more effective methods and technologies can be developed to help people improve brain function and cognitive ability. In general, based on maintaining a positive attitude and a healthy lifestyle, we can improve the quantity and quality of symmetrical synapses in the brain through continuous learning and training, thereby improving memory and learning ability, and laying a solid foundation for our future. It can be seen that we need to improve memory, and Cistanche can significantly improve memory because Cistanche is a traditional Chinese medicinal material with many unique effects, one of which is to improve memory. The efficacy of Cistanche comes from the various active ingredients it contains, including tannic acid, polysaccharides, flavonoid glycosides, etc. These ingredients can promote brain health in many ways.

Click know 10 ways to improve memory

The balance between these two systems is critical to maintaining a correct brain function. Likewise, the modulation of both types of synapses is also important to maintain a healthy equilibrium. 

Cerebral circuitry responds differently depending on the type of damage and the timeline of the injury. For example, promoting symmetric signaling following ischemic damage is beneficial only during the acute phase; afterward, it further increases the initial damage. 

Synapses can be also altered by players not directly related to them; the chronic and long-term neurodegeneration mediated by tau proteins primarily targets asymmetric synapses by decreasing neuronal plasticity and functionality. 

Dopamine represents the main modulating system within the central nervous system. Indeed, the death of midbrain dopaminergic neurons impairs locomotion, underlying the devastating Parkinson's disease. 

Herein, we will review studies on symmetric and asymmetric synapse plasticity after three different stressors: symmetric signaling under acute damage-ischemic stroke; asymmetric signaling under chronic and long-term neurodegeneration-Alzheimer's disease; symmetric and asymmetric synapses without modulation-Parkinson's disease.

Keywords: Alzheimer's disease; asymmetric synapses; dopamine; GABAergic transmission; glutamatergic transmission; Parkinson's disease; stroke; symmetric synapses; tau.

1. Introduction

At the end of the 19500s, E. G. Gray used electron microscopy to define two different types of synapses in the central nervous system (CNS): asymmetric and symmetric synapses [1]. Based on his achievements, asymmetric (or type I) synapses are defined by a postsynaptic density (PSD), thicker than the presynaptic fraction, whereas symmetric (or type II) synapses present a PSD similar in width to the presynaptic membrane. 

Subsequently, asymmetric and symmetric synapses were correlated to excitatory or inhibitory signaling, respectively [2]. Although controversial [3], nowadays this terminology is still being used to identify excitatory and inhibitory synapses along the CNS. 

As mentioned, the PSD is a high-density fraction in the postsynaptic membrane with different roles such as mediating the apposition of pre-and post-synaptic membranes, clustering postsynaptic receptors, or coupling the activation of these receptors to cellular signaling [4–6]. 

The PSD in asymmetric synapses is composed of membrane proteins (e.g., α-amino-3-hidroxi-5-metilo-4-isoxazolpropionic receptor [AMPAR], N-methyl-D-aspartate receptor [NMDAR], metabotropic receptors, ion channels and adhesion molecules), scaffold proteins (such as the postsynaptic density protein 95 [PSD-95]), and signaling proteins [6,7]. 

PSD-95 is the most abundant scaffold protein in postsynapses, where it plays a crucial role in organization by interacting with adhesion molecules, glutamate receptors, and signaling proteins through its PDZ domain [8,9]. 

Accordingly, high levels of PSD-95 are correlated with larger PSDs and enhanced synaptic strength [10]. In contrast, symmetric synapses display a different composition in their PSD, where gamma-aminobutyric acid (GABA) A (GABAA, ionotropic) and GABA B (GABAB, metabotropic) receptors are responsible for mediating inhibitory responses. 

Interestingly, the number of GABAA receptors at the membrane usually determines the strength of the inhibitory synaptic signaling [11]. Similarly to PSD-95, gephyrin plays an important role in the structure of the inhibitory PSD by clustering GABA receptors and acting as a scaffold protein [12,13]. 

Both asymmetric and symmetric PSDs are not fixed but constantly changing, reflecting the high plasticity present in this network. The strength of these synapses can be modified in a bidirectional way by mechanisms such as long-term potentiation (LTP) or long-term depression (LTD), among others [14]. Likewise, modulatory neurotransmitters can also influence and regulate synaptic transmission [15]. 

LTP and LTD are well-known forms of synaptic plasticity. Most of our knowledge about LTP/LTD came from reports of asymmetric synapses, where NMDA-mediated LTP/LTD is the most studied [14]. 

In excitatory synapses, LTP is induced only when both pre- and post-synaptic neurons are active, and the postsynaptic neuron must be already depolarized at the moment glutamate binds to NMDARs. This is important because it is needed to reach the highest calcium influx to activate intracellular signaling pathways underlying these synaptic modifications [16]. 

Contrary to LTP, LTD is generally induced by repeated activation of the presynaptic neuron without postsynaptic activity, which leads to a smaller NMDA-mediated calcium influx and synaptic endocytosis of AMPARs [16,17]. Regarding inhibitory transmission, LTP/LTD mechanisms are also present in inhibitory synapses throughout the brain [18]. 

Inhibitory LTP or LTD needs the presence of glutamatergic synapses, and therefore, the activation of corresponding glutamate receptors to trigger the underlying cellular mechanisms [19]. Neuromodulators are compounds that modify synaptic transmission by regulating the excitability of both pre-and post-synaptic neurons and the response of receptors to neurotransmitters [20]. 

Within neuromodulators, dopamine (DA) is one of the most studied because its functions are of such importance that deficits in dopaminergic (DAergic) signaling lead to neurological disorders [15]. Midbrain DAergic neurons represent the main source of DA in the CNS, the substantia nigra pars compacta (SNc) and the ventral tegmental area being two important centers providing a significant amount of DA to the basal ganglia (BG) and forebrain [21]. 

Through the activation of metabotropic receptors (D1-D5), DA can modify the excitability of neurons by regulating the voltage- or ligand-gated channels [15], as well as regulating the function and trafficking of GABA receptors, NMDARs, and AMPARs [22]. 

In this way, DA can affect different synaptic dynamics [23]. Both asymmetric and symmetric synapses have important roles in shaping the structural and functional outcomes of the brain. 

Therefore, the balance between excitation and inhibition is capital for a normal cerebral function. 

Here, we take advantage of Gray's definitions to review recent advances in the understanding of synaptic alterations at asymmetric and/or symmetric signaling under three different conditions: symmetric signaling following acute damage-stroke; asymmetric signaling in long-term neuronal degeneration- Alzheimer's disease; both signaling with no modulation-Parkinson's disease.

2. Ischemic Stroke

Stroke is becoming one of the most common causes of death in developed countries, representing the main cause of long-term disability due to the limited capacity of the human brain to repair. 

Ischemic stroke, the occlusion of a blood vessel leading to a lack of blood flux, has fatal consequences even in short-term blockages and it represents 85% of total cases in Europe [24,25]. 

Following the insult, two large areas can be distinguished: the ischemic core, necrotic tissue with irreparable damage; and the peri-infarct, or penumbra, an area containing hypoperfused tissue that is still viable for several hours and can be salvaged by restoration of the blood flow. Over the next few hours to days, this periinfarct tissue undergoes secondary damage by the activation of the ischemic cascade which eventually leads to neuronal death. 

The response to the damage varies depending on which cerebral area is affected, with the cortex and hippocampus arising as two of the most susceptible areas [26,27]. The timeline of neuronal death differs among these two areas, with cortical neurons displaying a quick death in comparison with hippocampal neurons that show a delayed death occurring 3–5 days following the insult [26]. 

This exposes the complexity of neuronal connections since every cortical microcircuit responds differently after damage, and the outcome following treatment may not be the same throughout the different cortical layers [28,29]. 

Two different phases can be distinguished from the onset of an ischemic insult, and each one shows how the imbalance between excitatory and inhibitory signaling can negatively affect neuronal/functional outcomes [30]. 

During the acute phase, under a hypoxic environment, there is a massive presynaptic release of glutamate that overactivates postsynaptic NMDARs. This leads to the entry of large amounts of Ca2+ during the first minutes to hours, which stimulates a variety of cellular processes that ultimately produce irreparable neuronal damage and cell death (Figure 1) [25,30]. 

Recently, Tanaka et al. [31] reported increased levels of glutamate by using MALDI mass spectrometry imaging in the peri-infarct area of a mouse model. In addition to this, the astroglial-mediated reuptake of glutamate is reduced following injury, further increasing extracellular levels of glutamate [26]. In such a situation, the enhancement of GABA signaling counterbalances the excitatory inputs promoting neuroprotection (Figure 1) [32]. 

Conversely, during the post-acute/chronic phase, GABA signaling is highly increased and limits neural repair by decreasing neuronal excitability and impairing LTP [33,34]. This occurs simultaneously with a rearrangement of cortical networks underlying neuronal plasticity by enhancing the ability to induce LTP throughout prolonged excitatory signaling during the first-week post-stroke [33,35,36]. 

Therefore, treatments blocking GABA signaling during this phase may represent promising therapies to help in the recovery of patients following stroke [28,34,37,38]. Overall, avoiding the transformation of the penumbra into infarcted tissue is a key target to overcome neuronal damage, and it may improve the outcome of patients after stroke. 

Besides, it seems pivotal to understand how and when the switch from acute to post-acute/chronic phase occurs in humans to tackle the distinct cellular mechanisms underlying neuronal damage over time. Achievements in this field will allow the translation from animal models to humans.

2.1. GABA Receptors

GABA signaling through the GABAA receptor is more relevant than the same mediated by GABAp receptors in the pathophysiology of stroke. Therefore, we will focus primarily on GABA receptors, only citing the most relevant information regarding GABAp receptors.

The different subunits forming ionotropic GABAA receptors determine the properties and location of receptors. These changes in subunit composition are responsible for the synaptic and extrasynaptic location of GABAA receptors, which mediate phasic (synaptic)and tonic (extrasynaptic) inhibition, respectively [32]. 

During phasic inhibition, GABA released from presynaptic terminals reaches the postsynaptic membrane where it binds to GABA receptors and triggers an inward chloride current, leading to the hyperpolarization of the neuron. 

This cellular mechanism represents a transient response defined by a rapid desensitization of the synaptic GABA, receptors, and the removal of extrasynaptic GABA by GABA transporters (GATs). 

On the other hand, tonic inhibition mediates a continuously inhibitory current controlling the neuronal membrane potential and thus its fire potential such GABAergic signaling is triggered when extrasynaptic GABAA receptors with high affinity and slow desensitization for GABA respond to either ambient GABA levels outside synapse or synaptic spillover of GABA. 

Regarding metabotropic GABA receptors, they are the main regulators of presynaptic glutamate release in excitatory neurons; they also control the activity of postsynaptic glutamate receptors [39].

In the GABAA receptors, trafficking to and from the plasma membrane only occurs at the extrasynaptic space, lateral diffusion being the main mechanism controlling their synaptic pool, and therefore the strength of symmetric signaling [32]. 

Based on their location, the clustering of GABAA receptors is modulated by gephyrin (synaptic site) or radixin (extrasynaptic site), and both scaffold proteins are positively regulated by phosphorylation, strengthen the clustering at the membrane [32,40,41]. 

Mele and colleagues [40] suggested that the dephosphorylation of α1 subunit-containing GABAA receptors is directly involved in their internalization, likely by losing the link with gephyrin, following in vitro ischemic damage. 

Likewise, it has been proposed that the calcium-mediated activation of calpain leads to the cleavage of the gephyrin lattice and subsequent reduction in the synaptic clustering of GABAA receptors in hippocampal neurons from rats under in vitro excitotoxic conditions [42]. 

Hence, ischemic conditions lead to decreased levels of phosphorylated GABAA receptors, as well as GABAB receptors, suggesting that this is the reason underlying the ischemia-induced endocytosis of receptors. Moreover, this decrease could also explain why GABAB receptors cannot counteract glutamate-mediated overexcitation [43,44]. 

Immediately after an ischemic event, large amounts of glutamate contribute to a strong activation of NMDARs that downregulates the expression of both GABAA and GABAB receptors through a phosphorylation process activated by high levels of Ca2+ (Figure 1) [32,43–46]. Accordingly, phasic GABA signaling is reduced in the first weeks after stroke [28,40]. 

This situation further increases neuronal depolarization and subsequent cellular damage. Recently, two proteomic studies have revealed increased levels of the GABA aminotransferase GABT, as well as reduced levels of GABA receptors and the excitatory amino acid transporter EAA2, in the infarct core area from postmortem tissue samples of stroke patients [47,48]. 

These results validate results from animal models by showing overall decreased GABAergic signaling (elevated catabolism of GABA and reduced GABA receptors) and increased glutamatergic signaling (reduced removal from synaptic cleft by EAA2). That is why the enhancement of GABA signaling at this point can exert a neuroprotective role by decreasing cellular excitability (Figure 1). 

Indeed, an early study by Costa and coworkers [49] revealed that the coactivation of both GABAA and GABAB receptors promoted neuroprotection in an in vitro model of ischemic stroke. Similarly, the activation of either GABAA or GABAB receptors separately also has prosurvival outcomes. Several studies have reported that the remaining GABAB receptors can be activated between days 1–3 post-stroke and this promotes neuroprotection [42,50]. 

Since the 19900s, the neuroprotective role of enhancing phasic GABA signaling at the acute phase has been studied throughout pharmacological treatments in both in vitro and in vivo models [39,51]. 

Likewise, some studies suggest the benefits of enhancing phasic GABA signaling during the chronic phase of stroke in humans [52,53]. It has been reported that phasic GABA signaling is increased in cortical pyramidal neurons during the chronic phase of stroke [29]. 

The pharmacological boost of α1 subunit-mediated currents at 3 days post-stroke promotes functional recovery by targeting cortical plasticity [29].

Although glutamate is excitotoxic during the acute phase following stroke, it plays a beneficial role during the recovery phase by inducing LTP [33,34]. Indeed, studies in humans have suggested that the stimulation of the penumbra cortex by boosting local excitability as soon as 7 days post-stroke improves functional outcomes [54]. 

However, there is an increase in extrasynaptic levels of GABA due to the reduction in the amount of astrogial GABA transporters on day 7 post-stroke in mice [28]. This event hyperpolarizes neurons at the penumbra area and negatively modulates the induction of LTP [32,34,55]. Indeed, a recent study using magnetic resonance spectroscopy showed that patients with a low excitatory–inhibitory ratio post-stroke had a worse motor outcome [56]. 

The application of pharmacological treatments negatively targeting either all α subunits or only α5 subunit mediated tonic GABA currents at 3 days post-stroke has shown significant behavioral recovery in mouse models [28,34,37]. 

Interestingly, it has been reported that there is a possible role of extrasynaptic GABAC receptors, a well-known subclass of GABAA receptors, in these increased tonic currents during post-acute and chronic phases. The application of antagonists targeting GABAC receptors from day 3 post-stroke improved the motor function of injured mice [38]. 

These results together suggest that the time window for the administration of an extrasynaptic GABAA receptor blocker without affecting its initial neuroprotective role is around 3 days after the infarct, at least in mice. Overall, the potentiation of symmetric signaling immediately after ischemic stroke counteracts the prominent excitatory cellular state promoting neuronal survival. 

Based on murine models, the acute phase lasts 3 days, and one of the most important questions to be solved is the exact duration of this phase in humans to replicate the results from animal models to patients. In contrast, during the post-acute and chronic phases, the rise in tonic GABAergic signaling has to be blocked to achieve a better functional outcome. 

Curiously, the potentiation of phasic inhibition is beneficial during the recovery state. It would be interesting to combine pro-GABA drugs during the acute phase and then change them progressively to both prophasic signaling and antitonic currents.

For more information:1950477648nn@gmail.com