Parkinson’s disease is caused by progressive damage to regions of the brain that regulate movement. This leads to a loss in nerve cells that produce a signaling molecule called dopamine, and causes patients to experience shakiness, slow movement and stiffness. When dopamine is released, it travels to a part of the brain known as the striatum, where it is received by cells called spiny projection neurons (SPNs), which are rich in a protein called LRRK2. Mutations in this protein have been shown to cause the motor impairments associated with Parkinson’s disease.

SPNs send signals to other regions of the brain either via a ‘direct’ route, which promotes movement, or an ‘indirect’ route, which suppresses movement. Previous studies suggest that mutations in the gene for LRRK2 influence the activity of these pathways even before dopamine signaling has been lost. Yet, it remained unclear how different mutations independently affected each pathway. To investigate this further, Chen et al. studied two of the mutations most commonly found in the human gene for LRRK2, known as G2019S and R1441C. This involved introducing one of these mutations in to the genetic code of mice, and using fluorescent proteins to mark single SPNs in either the direct or indirect pathway.

The experiments showed that both mutations disrupted the connections between SPNs in the direct and indirect pathway, which altered the activity of nerve cells in the striatum. Chen et al. found that individual connections were more strongly affected by the R1441C mutation. Further experiments showed that this was caused by the re-organization of a receptor protein in the nerve cells of the direct pathway, which increased how SPNs responded to inputs from other nerve cells.

These findings suggest that LRRK2 mutations disrupt neural activity in the striatum before dopamine levels become depleted. This discovery could help researchers identify new therapies for treating the early stages of Parkinson’s disease before the symptoms of dopamine loss arise.

Gain-of-function mutations in the leucine-rich repeat kinase 2 (LRRK2) gene represent the most common cause of familial Parkinson’s disease (PD) (Alessi and Sammler, 2018). Carriers are at risk for late onset PD, which is clinically indistinguishable from sporadic PD, consistent with a possibility of common disease mechanisms (Kluss et al., 2019; Italian Parkinson's Genetics Network et al., 2006; Haugarvoll et al., 2008; Di Maio et al., 2018). LRRK2 gene product is a large multi-domain protein with two catalytic domains: a GTPase (ROC-COR) domain and a serine/threonine-directed protein kinase domain. Pathogenic mutations are found predominantly in these two domains, suggesting that LRRK2 enzymatic activities are involved in PD pathogenesis (Cookson, 2010), (Esteves et al., 2014). Yet, how LRRK2 mutations in the two distinct functional domains contribute to PD pathogenesis and whether they act through a common mechanism is unknown. Enhanced LRRK2 kinase activity conferred by the G2019S (GS) mutation in the kinase domain is the most extensively studied property of mutant LRRK2 (Cookson, 2010), (Steger et al., 2016). Meanwhile, the R1441C (RC) substitution in the GTPase domain results in impaired GTP hydrolysis, which is thought to indirectly enhance kinase activity through mechanisms that remain to be determined (Nguyen and Moore, 2017), (Xiong et al., 2010).

Despite remaining questions, the last decade marks extensive progress in our understanding of LRRK2 function. This kinase is highly expressed in the spiny projection neurons (SPNs) of the striatum (Nguyen and Moore, 2017; West et al., 2014; Parisiadou et al., 2014). LRRK2 expression peaks in a developmental time window of extensive glutamatergic excitatory synapse formation, suggesting that LRRK2 may regulate the development or function of excitatory synaptic networks. Consistently, several lines of evidence suggest that loss of LRRK2 alters striatal circuits during postnatal development (Parisiadou et al., 2014), and the GS pathogenic mutation increases glutamatergic activity in cultured cortical neurons (Beccano-Kelly et al., 2015) as well as in acute striatal slices (Matikainen-Ankney et al., 2016), (Volta et al., 2017). Recent studies assign a critical role of LRRK2 in presynaptic terminal vesicle function (Pan et al., 2017). Here, the GS mutation impairs presynaptic glutamatergic release, suggested to underlie changes in glutamatergic activity of striatal neurons (Volta et al., 2017). The potential postsynaptic function of LRRK2 remains less well-characterized. We have previously shown that the RC mutation impedes normal striatal protein kinase A (PKA) signaling, which in turn results in increased GluA1 phosphorylation in developing SPNs, consistent with a postsynaptic mechanism of action (Parisiadou et al., 2014). Similarly, glutamate receptor trafficking perturbations were observed in GS knock-in (KI) mice in response to plasticity induction protocols (Matikainen-Ankney et al., 2018). Furthermore, although an increase in spontaneous excitatory postsynaptic currents has been reported for the dorsomedial striatum, a recent report failed to show this phenotype for the ventral striatum (Huntley, 2020), despite LRRK2 expression in that region (West et al., 2014), (Giesert et al., 2013). These observations suggest that LRRK2 mutations may shape the corticostriatal synaptic function in a synapse-, cell- and area-specific manner. Overall, despite the links between LRRK2 and glutamatergic synapse dysfunction, the field currently lacks a coherent framework for understanding how the two distinct LRRK2 mutations selectively alter synaptic function in specific cell types.

Given the complementary role of direct and indirect striatal pathways in behavior (Kravitz et al., 2010; Fieblinger et al., 2014; Kozorovitskiy et al., 2012) the lack of pathway specificity in prior studies limits our understanding of disease related mechanisms associated with LRRK2 mutations. Previous studies did not compare the dysfunction of two LRRK2 mutations which are found in distinct LRRK2 domains and confer divergent biochemical properties to the kinase, choosing instead to focus on the one mutation or the other. Earlier reports have mainly focused on the GS pathogenic mutation, and whether the molecular mechanisms underlying pathology across the two most common mutations remain unknown. In addition, the phenotype of LRRK2 mutant models is subtle and corresponds to a moderate susceptibility for PD. Therefore, refined tools are required to distinguish the early pre-pathology functional abnormalities. We have taken the approach of combining molecular, anatomical and electrophysiological approaches that capture global aspects of LRRK2 function in the striatum, but also single synapse-specific effects, in case abnormalities are associated with specific synapse subtypes.

Here, we undertook a systematic synapse function and structure analysis in two different mutant LRRK2 mouse lines to evaluate the contribution of this kinase mutations to SPN synapses across direct and indirect pathways. Using a combination of subcellular fractionation biochemistry, super-resolution imaging, and two-photon laser scanning microscopy with whole-cell physiology approaches, we found a critical role for LRRK2 RC, and to a lesser extent GS mutation, in organizing the structure and function of the SPN excitatory synapses, particularly for dSPNs.

In the present study, we characterized synaptic dysfunctions caused by mutant LRRK2 (RC and GS) in pathway-identified SPNs. To our knowledge, this is the first comparative approach focusing on more than one PD related LRRK2 mutation and employing both global and single synapse approaches for the study of LRRK2 driven striatal remodeling. By studying RC and GS KI mouse lines side by side, we were able to demonstrate that the two most common LRRK2 gain-of-function pathogenic mutations (Hernandez et al., 2016) alter the function of SPN excitatory synapses in largely similar ways, with several potentially important differences. The observed changes were frequently stronger for the RC mutations, and more exaggerated in the direct pathway. For example, while whole cell electrophysiology recordings revealed decreases in the mESPCs frequency across both +/RC and +/GS mice, two-photon dual laser glutamate uncaging and imaging, combined with whole-cell electrophysiology, demonstrated larger amplitude in uEPSCs selectively for +/RC dSPNs. This observation paralleled higher synaptic GluA1 receptors levels in the same subtype +/RC SPNs (Figure 6G).

Based on the current knowledge, it remains unclear why the RC mutation is associated with somewhat more pronounced effects on sculpting striatal synapses. The GS mutation, which has been the main focus of the current literature, is found in the kinase domain of LRRK2, whereas the RC mutation is located in the GTPase domain of the protein (Paisán-Ruiz et al., 2013), (Cookson, 2012). It has been previously proposed that all pathogenic mutations lead to increased LRRK2 kinase activity, although the mechanism by which RC does this still remains unclear (Alessi and Sammler, 2018; Nguyen and Moore, 2017). Moreover, it is not known whether aberrant LRRK2 substrate phosphorylation is the predominant pathogenic mechanism in LRRK2 mediated striatal changes. Recent findings have revealed a subset of Rab family of proteins as the long awaited bona fide LRRK2 substrates (Steger et al., 2016). Notably, the RC mutation, mainly in the context of heterologous cell lines, leads to higher increase in Rab phosphorylation compared to the GS mutation, which is localized to the kinase domain (Liu et al., 2018), (Purlyte et al., 2018). Similarly, the evidence of increased synaptic PKA activities was observed in +/RC and not +/GS striatal synaptic fractions. This increased PKA activity in the RC synapses is expected to positively correlate with elevations in dSPNs signaling (Zhai et al., 2019). Specifically, phosphorylation of GluA1 at Ser 845 by PKA facilitates the targeting of the receptors to extrasynaptic membranes and their ‘priming’ for synaptic insertion and this results in elevated GluA1 synaptic incorporation (Diering and Huganir, 2018). Indeed, our biochemical and SIM imaging data in RC mice support this notion. In contrast to dSPNs, PKA-driven signaling requirements for iSPNs are more complex, due to the involvement of adenosine. This molecule can be released by neurons or glia (Surmeier et al., 2007), (Zhang et al., 2019), complicating predictions for PKA involvement in mutant LRRK2 function in iSPNs.

Several prior reports demonstrate a LRRK2 mediated presynaptic regulation of glutamatergic transmission (Matikainen-Ankney et al., 2016; Volta et al., 2017; Beccano-Kelly et al., 2015; Piccoli et al., 2011), while emerging evidence emphasizes a postsynaptic role for LRRK2 (Parisiadou et al., 2014; Matikainen-Ankney et al., 2016). Our previous and current findings showed that LRRK2 contributes to glutamatergic synaptic functions by directing PKA signaling events in SPNs, leading to altered GluA1 synaptic incorporation in the striatum of RC mice (Parisiadou et al., 2014). Despite the elevated GluA1 levels in the synapses of +/RC dSPNs, there were no alterations in mean mEPSCs amplitude in these neurons. However, cumulative probability analysis demonstrated that the amplitude shifted toward larger values in the +/RC dSPNs, suggesting an inhomogeneity of synaptic function, where a fraction of synapses exhibit larger GluA1-dependent responses and single-synapse uncaging-evoked EPSCs. This scenario, on top of overall dampening of mEPSC frequency, is expected to bias mutant dSPN responses to be driven by a narrower set of glutamatergic inputs than is normally the case. Overtime, a small bias could be amplified through the recurrent circuitry of basal ganglia loops (Kozorovitskiy et al., 2012). While there are some differences in the age of preparation and in recording conditions, our consistent finding of substantial miniature EPSC frequency decreases for both mutations in pathway-identified SPNs are in disagreement with prior recordings of spontaneous events in the GS mutant mice. One recent report showed elevations in spontaneous EPSCs events frequency in GS KI mice at 1–3 months (Volta et al., 2017), while another reported changes in spontaneous but not miniature events with the GS mutation in pre-weaning mutants (Matikainen-Ankney et al., 2016), although recordings were primarily performed in a mixed population of direct and indirect pathway SPNs, and neither study thoroughly compared the two mutations. Such differences in spontaneous event frequency point to a potential circuit-level compensatory mechanism that may be driven by disturbances in a subset of SPN excitatory synapses. Surprisingly, in the presence of clear functional and nano-architecture abnormalities, aggregate dendritic spine density and morphology, at least at the ages we evaluated, appeared normal. One possible explanation for this mismatch that requires further investigation is the possibility of higher occurrence of nonfunctional or differently functioning spines in LRRK2 mutant SPNs.

Given the critical role of LRRK2 in excitatory glutamatergic synapses (Parisiadou et al., 2014; Volta et al., 2017; Matikainen-Ankney et al., 2016), a more nuanced understanding of LRRK2-mediated synaptic alterations should facilitate the search for more targeted PD therapies. Here, we focused primarily on interrogating cell type specific LRRK2-based responses. Why does this pathway specificity matter? It is well-established that dopamine loss causes pathway-specific morphological and functional changes in SPNs (Kravitz et al., 2010; Fieblinger et al., 2014; Gertler et al., 2008). Moreover, dSPNs and iSPNs exhibit opposing PKA pathway signaling properties after dopamine receptor activation (Gerfen and Surmeier, 2011; Surmeier et al., 2007). Given the critical role of LRRK2 in synaptic PKA activities (Parisiadou et al., 2014; Tozzi et al., 2018b), these mutations are poised to have pathway specific effects and present distinct opportunities for pathway-targeted therapies. Over the past years, a number of transgenic mouse models was generated to study LRRK2 function (Volta and Melrose, 2017; Xiong et al., 2017); however, the results were found to be inconsistent across studies. Gene-targeted mutant LRRK2 KI mice represent the most physiologically relevant model to investigate LRRK2 mediated alterations and unravel disease mechanisms. Here, we attempt to synthesize and further the existing knowledge by employing a comparative approach focusing on two distinct mutations, combined with a powerful suite of techniques allowing for both global and single synapse study of LRRK2 SPNs.

The clinical phenotypes that define PD arise after a substantial loss of nigrostriatal dopamine signaling. Thus, the identification of pre-symptomatic dysfunctions offers a potential window of opportunity for the development of neuroprotective therapies in PD. Human asymptomatic LRRK2 mutation carriers represent an appropriate population to define these preclinical symptoms. Indeed, emerging evidence suggests that asymptomatic LRRK2 mutation carriers do show subtle motor and non-motor symptoms, including alterations of corticostriatal circuit organization, in comparison to asymptomatic non-carriers (PPMI Investigators et al., 2020; LRRK2 Ashkenazi Jewish Consortium et al., 2015). Accordingly, cellular and synaptic dysfunctions in etiologically relevant LRRK2 mutant KI mice allow investigations of the early events that precede neuronal death and may be predictive of future dysfunction. Several studies have suggested a central role for LRRK2 in striatal SPNs (Volta et al., 2017), (Parisiadou et al., 2014; Xenias, 2020). Here, we show that the presence of LRRK2 mutations can influence SPN function in a pathway-specific context, in the absence of dopamine neurodegeneration. Examining PD-relevant cellular functions in the absence of DA depletion represents a move away from the classical ways of studying PD in small rodent models, where basal ganglia cellular and network properties have been examined using several methods for dopamine depletion (Gerfen and Surmeier, 2011; Kreitzer and Malenka, 2008). While there is evidence that at first iSPNs show the primary structural and functional synaptic and dendritic changes in response to dopamine loss (Gerfen, 2006; Gertler et al., 2008; Day et al., 2006; Villalba et al., 2009), with time both SPNs types undergo substantial adaptations (Suarez et al., 2018), (Gagnon et al., 2017). Here, we find that some early changes in LRRK2 mutant dSPNs – including those observed at the single synapse level – are poised to contribute to the fragility of the system to lower levels of DA loss/variation. Because the well-described recurrent circuitry of the basal ganglia (Kozorovitskiy et al., 2012), (Kravitz et al., 2010; Oldenburg and Sabatini, 2015) enables the output of direct and indirect pathways to feed back to regulate cortico-striatal glutamate release, minor synaptic defects in LRRK2 mutant SPNs could be amplified over time, contributing to the life-time risk of the disorder. The presence of early corticostriatal alterations in LRRK2 carriers (LRRK2 Ashkenazi Jewish Consortium et al., 2015; Vilas et al., 2015; the Barcelona LRRK2 Study Group et al., 2016), along with the evidence for finer scale synaptic dysfunctions reported in this study, open the possibilities for future personalized medicine approaches that take into account the specific LRRK2 mutation and emphasize protecting the health of striatal neurons prior to potential DA losses.

All data generated during this study are included in the manuscript and supporting files.

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Author details

1. Chuyu Chen

   Department of Pharmacology, Feinberg School of Medicine, Northwestern University, Chicago, United States

   Contribution

   Conceptualization, Data curation, Formal analysis, Validation, Investigation, Visualization, Methodology, Writing - original draft, Writing - review and editing

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0001-5666-5173

2. Giulia Soto

   Department of Neurobiology, Northwestern University, Chicago, United States

   Contribution

   Formal analysis, Validation, Investigation, Visualization, Methodology, Writing - review and editing

   Competing interests

   No competing interests declared

3. Vasin Dumrongprechachan

   Department of Neurobiology, Northwestern University, Chicago, United States

   Contribution

   Formal analysis, Methodology, Writing - review and editing

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0001-5890-6778

4. Nicholas Bannon

   Department of Neurobiology, Northwestern University, Chicago, United States

   Contribution

   Data curation, Formal analysis, Validation, Visualization, Methodology, Writing - review and editing

   Competing interests

   No competing interests declared

5. Shuo Kang

   Department of Pharmacology, Feinberg School of Medicine, Northwestern University, Chicago, United States

   Contribution

   Formal analysis, Methodology, Writing - original draft, Writing - review and editing

   Competing interests

   No competing interests declared

6. Yevgenia Kozorovitskiy

   Department of Neurobiology, Northwestern University, Chicago, United States

   Contribution

   Conceptualization, Resources, Data curation, Software, Formal analysis, Supervision, Funding acquisition, Validation, Investigation, Visualization, Methodology, Writing - original draft, Project administration, Writing - review and editing

   For correspondence

   Yevgenia.Kozorovitskiy@northwestern.edu

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0002-3710-1484

7. Loukia Parisiadou

   Department of Pharmacology, Feinberg School of Medicine, Northwestern University, Chicago, United States

   Contribution

   Conceptualization, Resources, Data curation, Software, Formal analysis, Supervision, Funding acquisition, Validation, Investigation, Visualization, Methodology, Writing - original draft, Project administration, Writing - review and editing

   For correspondence

   loukia.parisiadou@northwestern.edu

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0002-2569-4200

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