Symmetric And Asymmetric Synapses Driving Neurodegenerative Disorders Part 3

4.1. Symmetric Synapses

The majority of the nuclei are inhibitory, so GABAergic innervations represent the main system to regulates the firing rate and the pattern of neuron responses within the BG, such as hyperpolarizing the membrane potential that resets the pacemaking activity of neurons [145–147].

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4.1.1. The Striatum-STR

The STR comprises the largest integrating nucleus for cortical and thalamic inputs (see next subsection "asymmetric synapses" for more information). The main cell population in the STR is the GABAergic spiny projection neurons (SPNs), with several classes of other GABAergic and cholinergic interneurons [148,149]. 

SPNs process afferent information to BG in direct (d) or indirect (i) pathways, which are defined by two different types of SPNs: dSPNs and iSPNs, respectively (Figure 4) [150,151]. dSPNs express D1 receptors and project directly to SNr/GPi, whereas GPe and STN relay the information from iSPNsexpressing D2 receptors to SNr/GPi (Figure 4) [150,151]. 

Accordingly, these different pathways give rise to opposite motor outputs, the release of GABA and a subsequent decrease in the activity of SNr/GPi neurons through the activation of dSPNs that reduces tonic inhibitory outputs to downstream motor regions and promotes movement; and the activation of iSPNs that produces an excitatory effect on SNr/GPi neurons by disinhibiting mechanisms and results in inhibiting movement [152].

4.1.2. The External Segment of the Globus Pallidus-GPe

The GPU is composed of two main subtypes of neurons, the prototypic and arkypallidal neurons [153]. The first projects downstream to STN and SNr nuclei, and upstream to the STR; whereas the latter exclusively projects to the STR, being the most important source of GABA (Figure 4) [154]. 

Projections from GPe neurons to the cortex and thalamus have been also reported [155]. The inhibition provided by prototypic neurons is key to resetting the autonomous activity of STN neurons [156]. 

Likewise, GPe neurons are the receivers of GABAergic extrinsic innervations from iSPNs (the majority of them) and dSPNs, intrinsic innervations from collaterals of prototypic neurons to other GPe neurons, and interconnections between prototypic neurons (Figure 4) [157,158]. 

Moreover, arkypallidal neurons integrate signals from dSPNs, iSPNs, and STN [158]. Both short-term facilitation (STF) and short-term depression (STD) can be found at extrinsic synapses, while intrinsic synapses present STD [159,160].

4.1.3. The Substantia Nigra Pars Reticulate-SNr

The SNr operates as an integrating nucleus, as each SNr neuron receives afferents from different origins such as dSPNs, the GP, and the STN (Figure 4). Symmetric synapses from STR and GPe display opposite mechanisms as STR–SNr inhibitory postsynaptic currents (IPSCs) exhibit STF, whereas GP–SNr IPSCs are influenced by STD [161]. 

SNr neurons display a significant level of spontaneous firing rate that allows a tonic inhibition of downstream motor areas (Figure 4) [162,163]. They present high collateralization and receive solid inhibitory inputs, acting through both ionotropic (GABAA) and metabotropic (GABAB) receptors, even during a strong activation [164–166]. 

Four types of GABAergic neurons projecting to different targets can be found in the SNr, the thalamus being the one that receives the majority of SNr innervations [167,168].

4.1.4. Healthy and Pathological DA Modulation in Symmetric Synapses

STR is the main target of nigral DAergic innervation [144]. As previously mentioned, dSPNs and iSPNs express D1 and D2 receptors, respectively, which gives rise to opposite motor outputs following DA release. 

Upon DA release, dSPNs increase their activity through D1 receptor activation, whereas D2 receptors mediate the decreased activity of iSPNs (Figure 4) [169,170]. The effect is the overactivation of the direct pathway compared to the indirect one, disinhibiting the thalamus and initiating movement. Therefore, DA modulates the synaptic and intrinsic properties of STR neurons by activating distinct DA receptors (Figure 4). 

Recently, an interesting study has revealed that astrocytic GATs play a critical role in the regulation of striatal DA release by removing extrasynaptic GABA spillover, decreasing tonic inhibition, and therefore, promoting DA release [171]. 

Indeed, there is an inadequate reduction in GATs that further impairs DA output at the early steps of the disease [171]. Following full DA depletion, the overall activity of dSPNs decreases and there is a loss of spine density [152]. 

Consequently, this disinhibits GABAergic projections from SNr/GPi neurons [172]. In contrast, the lack of DA increases the excitability of iSPNs by eliminating the inhibition through D2 receptors, even when there is also a reduction in spine density (Figure 4) [152,170]. Furthermore, the lack of DA has been also related to a higher GABA production, as shown by a nuclear magnetic resonance spectroscopy study in the striatum of a rat model [173]. 

Altogether, this disinhibits STN activity leading to a higher excitation of SNr/GPi [170,174]. The resulting outcome is the imbalance between direct and indirect pathways shown by the reduction in motor outputs (paucity and slowness of movements), exposing the capital need of having a coordinated striatal activity [175,176]. 

DA modulates the excitability of GPe neurons, the D2 receptor being the one that is present in all GPe neurons, although prototypical neurons show higher levels of D2 receptors than arkypallidal neurons [177]. 

Accordingly, activation of presynaptic D2 receptors reduces the GABAergic pallidosubthalamic innervations, decreasing the strength of this connection [178]. Under the Parkinsonian state, the activity of prototypic cells is likely disrupted by the hyperactivity of iSPNs, as previously mentioned (Figure 4) [179,180]. However, this is not an obstacle to seeing an increased GPe–STN GABAergic transmission in an NMDA-mediated manner [181,182]. 

Similarly, the GABAergic inhibition from arkypallidal neurons to STR is increased under DA depletion, even when their excitability is reduced (Figure 4) [183,184]. 

As previously stated, both STF and STD can be seen in striato-pallidal and pallido-pallidal synapses, respectively [159,160]. Besides their opposite roles, STF and STD also have the difference that only the STF strength is modulated by presynaptic D2 receptors, resulting in a decreased GABA release [185]. Additionally, GABAergic transmission can be regulated by reducing the amplitude of GABAA-mediated postsynaptic currents through the activation of D4 receptors. 

Similarly, intrinsic connections can also reduce the postsynaptic firing rate [186]. Only the study from Stefani and colleagues [187] shed light on action mechanisms underlying the reduced excitability seen in GPe neurons. There, the authors showed that the activation of D2 receptors inhibits GPe excitability in a protein-kinase-C-dependent manner.

Functions of the SNr are also modulated by DA through the expression of different receptors in SNr neurons (Figure 4). Although D1 receptors are the ones more expressed, the presence of D4 and D5 receptors has been also reported [188–190]. The study by Zhou et al. [191] revealed that the activation of D1 receptors depolarizes SNr neurons, and therefore excites them. 

In contrast, the pharmacological blockade of D1 or D2 receptors leads to the hyperpolarization of SNr neurons, and this is similar to what was seen in recordings from rodents with DA depletion [192,193]. For STR–SNr synapses, there is an increase in IPSCs amplitude that is likely driven by both dysfunctional GABAB receptors and a presynaptic reduction in GABA release [194]. 

Regarding synaptic regulation, presynaptic D4 receptor activation reduces the transmission in GPe–SNr connections, whereas presynaptic D1 receptors mediate the increase in GABAergic signaling [195,196].

4.2. Asymmetric Synapses
4.2.1. The STR

The STR integrates cortical and thalamic excitatory information, making contact with the spine heads of GABAergic SPNs (Figure 4) [149,197]. Within the STR, cortical and thalamic terminals can be differentiated by the distinct expression of vesicular glutamate transporter 1 (vGLUT1) and vesicular glutamate transporter 2 (vGLUT2), respectively [198]. 

These excitatory inputs are key to hyperpolarizing SPN neurons, which subsequently allows the firing of their action potentials (APs) [199,200]. Both dSPNs and iSPNs express AMPA and NMDA receptors, as well as metabotropic glutamate receptors (mGluRs) that mediate synaptic transmission and LTP/LTD [201]. 

In dSPNs, the activation of NMDA and D1 receptors is responsible for the LTP induction, whereas LTD induction is mediated by muscarinic acetylcholine M4 and mGluR5 receptors [202,203]. 

On the other hand, LTP induction in iSPNs is mediated by the activation of NMDA and A2A receptors, whereas LTD is induced by postsynaptic D2 receptors and mGluR5 receptors [202].

4.2.2. The Subthalamic Nucleus-STN

Similarly to STR, the STN receives monosynaptic inputs from the cerebral cortex through the hyperdirect pathway (Figure 4) [197]. Subsequent AMPAR/NMDA-mediated postsynaptic excitatory currents (EPSC), along with GPe inhibition, regulate the ability of STN neurons to fire APs spontaneously [182]. 

These antagonistic inputs regulate the firing rate and pattern of STN transmission, and changes in the firing pattern are considered a hallmark of PD [204,205]. 

In contrast to the inhibitory STR, STN neurons are glutamatergic and project simultaneously to the GPe and SNr/GPi (Figure 4). Concretely, activation of STN provides two different outcomes: strong and sustained excitation of prototypic cells leading to the disinhibition of SPNs, and brief, excitation of arkypallidal, implying a short-time inhibition onto SPNs (Figure 4) [158,206]. 

Regarding SNr, STN innervations represent the main excitatory inputs, triggering monosynaptic EPSCs and increasing GABAergic signaling in downstream motor areas [162,207].

4.2.3. Healthy and Pathological DA Modulation in Asymmetric Synapses

DAergic innervation in the STR is involved in two capital aspects: regulating LTP of cortiostriatal synapses and also regulating the functional specificity of STR neurons in response to cortical and thalamic afferents [208]. 

Accordingly, DAergic denervation promotes the loss of cortico- and thalamo-striatal terminals, leading to a dysregulation of activity between direct and indirect pathways as well as important changes in LTP and LTD (Figure 4) [151,208,209]. 

Indeed, the death of nigral DAergic neurons reverses the strength of thalamic inputs to dSPNs and iSPNs by enhancing thalamostriatal inputs only to iSPNs, therefore driving asymmetric activation of basal ganglia (Figure 4) [210]. 

As previously mentioned, LTP and LTD are present in striatal SPNs, and this bidirectional synaptic plasticity is altered in the Parkinsonian state [209,211]. Without DA, dSPNs lose LTP due to the absence of D1 receptor activation, similar to the lack of LTD in iSPNs because of a lack of D2 receptor activation [202]. 

These PD-associated changes give rise to a scenario where dSPNs only exhibit LTD and iSPNs only exhibit LTP, leading to a disruption between dSPNs and iSPNs activity [211]. DA release has a main role in the function of STN neurons by regulating synaptic transmission as well as the strength of cortico-subthalamic inputs, therefore, lacking DA modulation has dramatic consequences in locomotion [204,212]. 

D2 and D5 receptors are the ones with high levels of expression on the STN neuron membrane, and the activation of each one has different outcomes for their firing rate (Figure 4) [15,213]. Previous results have revealed that D2 activation increases the firing discharge of STN neurons by depolarizing the membrane potential [214]. 

The activation of D5 receptors, however, triggers different conductance depending on the mode of discharge of STN neurons [215]. Hyperpolarized STN neurons fire bursts of APs and D5 activation prolongs burst duration [216]. In depolarized STN neurons, D5 activation increases the firing rate of single and tonic APs [217]. 

More recently, it has been shown that the activation of D5 receptors in STN neurons can modulate cortical inputs by depressing AMPAR-mediated EPSC [214]. Following DAergic denervation, STN neurons lose their autonomous pacemaking due to both increased inputs from iSPNs to GPe neurons that disinhibits STN neurons, and excessive activation of NMDARs [218] even when the cortical glutamatergic innervations are significantly reduced (Figure 4) [219–221]. 

This fact, and probably alterations in other channels such as the potassium/sodium hyperpolarization-activated cyclic nucleotide-gated ion channel 2 (HCN2) [222], allows a pathological hyperactive state for STN neurons with rhythmic and synchronous bursts of APs [223]. Under this state, there also is a strengthened connection between GPe and STN that is mediated by an excessive activation of NMDARs in the STN [176,181]. 

Although this can be contradictory, it can be explained since STN neuron activity is off-phase to GPe activity and in-phase to cortical activity [224] so it is expected that GPe–STN inhibitory inputs are less effective in suppressing cortical excitation [225]. 

Regarding SNr, dopamine receptors D1 and D2 have opposite roles in modulating EPSC amplitude: the D1 receptor acts as an enhancer, while the D2 receptor decreases it [226]. 

The presence of LTD at STN–SNr synapses, induced by the activation of postsynaptic D1 receptors, has also been reported. During this LTD, endocytosis of AMPARs mediated by NMDARs depresses EPSC amplitude [214]. In the absence of dopamine, STN–SNr LTD is completely depleted leading to an increased synaptic transmission in the STN–SNr circuitry [227,228].

5. Conclusions

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 correct cerebral function. 

Besides, even after a particular damage, the progression of the disease defines the response of circuitries; something beneficial at the beginning becomes negative later. 

In this regard, it has been described that promoting symmetric signaling following cerebral ischemia 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; in Alzheimer's Disease, the chronic and long-term neurodegeneration mediated by tau targets primary asymmetric synapses, decreasing neuronal plasticity and functionality. 

Indeed, the death of midbrain dopaminergic neurons impairs locomotion, underlying Parkinson's disease. Since symmetric and asymmetric synapses play an important role in the pathophysiology of several neurological disorders, such as stroke, Alzheimer's, or Parkinson's Disease, further studies are needed to elucidate the underlying molecular mechanisms that could lead to the development of new therapeutic targets for these devastating diseases.

Author Contributions: Conceptualization, D.R.-S., J.M.A., A.O., and T.S.; resources, T.S.; writing- original draft preparation, D.R.-S., A.O., and T.S.; writing-review and editing, D.R.-S., A.C., M.A.-N., A.P.-F., L.V.-V., J.C.-C., Y.L., J.M.P.-P., J.M.A., A.O. and T.S.; supervision, T.S.; funding acquisition, D.R.-S., A.C., and T.S. All authors have read and agreed to the published version of the manuscript.

Funding: This study was partially supported by grants from the Xunta de Galicia (TS: IN607A2018/3, TS: IN607D 2020/09, AC: IN606A-2021/015 & DRS: IN606B-2021/010), and Science Ministry of Spain (TS: RTI2018-102165-B-I00, TS: RTC2019-007373-1). Furthermore, this study was also supported by grants from the INTERREG Atlantic Area (TS: EAPA_791/2018_ EURO ATLANTIC project), INTER-REG V A España Portugal (POCTEP) (TS: 0624_2IQBIONEURO_6_E), and the European Regional Development Fund (ERDF). 

Moreover, MAN (IFI18/00008) is the recipient of an iPFIS contract, and TS (CPII17/00027) is the recipient of a research contract from the Miguel Servet Program from the Instituto de Salud Carlos III. The funders had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Conflicts of Interest: The authors declare no conflict of interest.

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