Our brain contains over a 100 billion nerve cells or neurons, and each of them is thought to connect to over 1,000 other neurons. Together, these cells form a complex network to convey information from our surroundings or transmit messages to designated destinations. This circuitry forms the basis of our unique cognitive abilities.

In the cerebral cortex – the largest region of the brain – two main types of neurons can be found: projection neurons, which transfer information to other regions in the brain, and interneurons, which connect locally to different neurons and harmonize this information by inhibiting specific messages. The over 20 different types of known interneurons come in different shapes and properties and are thought to play a key role in powerful computations such as learning and memory.

Since interneurons are hard to track, it is still unclear when and how they start to form and mature as the brain of an embryo develops. For example, one type of interneurons called the neurogliaform cells, have a very distinct shape and properties. But, until now, the origin of this cell type had been unknown.

To find out how neurogliaform cells develop, Niquille, Limoni, Markopoulos et al. used a specific gene called Hmx3 to track these cells over time. With this strategy, the shapes and properties of the cells could be analyzed. The results showed that neurogliaform cells originate from a region outside of the cerebral cortex called the preoptic area, and later travel over long distances to reach their final location. The cells reach the cortex a few days after their birth and take several weeks to mature.

These results suggest that the traits of a specific type of neuron is determined very early in life. By labeling this unique subset of interneurons, researchers will now be able to identify the specific molecular mechanisms that help the neurogliaform cells to develop. Furthermore, it will provide a new strategy to fully understand what role these cells play in processing information and guiding behavior.

Cortical microcircuit function relies on the coordinated activity of a variety of GABAergic interneuron subtypes, which play critical roles in controlling the firing rate of glutamatergic pyramidal neurons, synchronizing network rhythms and regulating behavioral states (Cardin et al., 2009; Fu et al., 2014; Kepecs and Fishell, 2014; Pfeffer et al., 2013; Pi et al., 2013; Pinto and Dan, 2015; Sohal et al., 2009; Zhang et al., 2014). Different subtypes of cortical interneurons (INs) emerge during development and their specification arises through the complex interaction of cell-intrinsic mechanisms and cell-extrinsic cues (Bartolini et al., 2013; Fishell and Rudy, 2011; Huang, 2014; Kessaris et al., 2014). Cortical INs are generated in a variety of subpallial regions and the combinatorial expression of transcription factors (TFs) in these domains is believed to play a critical role in their fate specification (Kessaris et al., 2014; Anastasiades and Butt, 2011; Flames et al., 2007; Wonders and Anderson, 2006). The largest fraction (about 60–70%) of cortical INs is generated from NKX2.1-expressing progenitors located in the medial ganglionic eminence (MGE) (Butt et al., 2008; Xu et al., 2008) and their specification is under the control of the TFs LHX6 (Du et al., 2008; Liodis et al., 2007) and SOX6 (Azim et al., 2009; Batista-Brito et al., 2009). MGE-derived INs develop into fast-spiking parvalbumin (PV)+ basket and chandelier cells, as well as into Martinotti and multipolar somatostatin (SST)+ INs (Butt et al., 2008; Xu et al., 2008; Du et al., 2008; Butt et al., 2005; Fogarty et al., 2007; Taniguchi et al., 2013). The second largest fraction of cortical INs arises from the caudal ganglionic eminence (CGE) (Miyoshi et al., 2010; Nery et al., 2002) and expresses TFs such as PROX1, SP8 and NR2F2 (Cai et al., 2013; Ma et al., 2012; Miyoshi et al., 2015; Rubin and Kessaris, 2013). CGE-derived INs also express the ionotropic serotonin receptor 3A (5-HT_3AR) and give rise to a large diversity of INs, including reelin+ cells, vasointestinal peptide (VIP)+/calretinin+ bipolar cells and VIP+/cholecystokinin+ basket cells (Miyoshi et al., 2010; Armstrong and Soltesz, 2012; Prönneke et al., 2015; Lee et al., 2010; Murthy et al., 2014; Vucurovic et al., 2010). Finally, lineage-tracing experiments using Hmx3 (Nkx5.1)-Cre (Gelman et al., 2009) and Dbx1-Cre driver lines (Gelman et al., 2011) have shown that a small fraction (about 10%) of cortical INs originate from the preoptic area (POA) (Gelman et al., 2009; Gelman et al., 2011).

Among cortical INs, neurogliaform cells (NGCs) display unique characteristics. They represent the main source of ‘slow’ cortical inhibition by acting on metabotropic GABA_B receptors (Tamás et al., 2003), and are thought to be key effectors of a powerful inhibitory circuit recruited by long-range connections such as interhemispheric and thalamic projections (Craig and McBain, 2014; Palmer et al., 2012; De Marco García et al., 2015). Whether the current description of NGCs captures an IN subtype related to a distinct developmental specification process is unclear. Here we used in vivo genetic lineage-tracing to follow the developmental origin and trajectory of NGCs. We found that they originate from a distinct pool of 5-HT_3AR-expressing Hmx3+ cells located in the rostral POA region, ventrally to the anterior commissure. In the embryonic POA, Htr3a-GFP+ INs in the Hmx3+ domain expressed CGE-enriched TFs such as PROX1 and NR2F2, but only rarely, if not, MGE-related TFs such as NKX2.1 or LHX6. In the cortex, Hmx3-derived Htr3a-GFP+ INs expressed markers of CGE-derived INs such as NPY and/or reelin, as well as CGE-enriched TFs such as SP8, NR2F2 and PROX1, but neither MGE-specific markers such as PV or SST nor TFs such as LHX6 or SOX6. Finally, single-molecule in situ hybridization and electrophysiological recordings followed by post hoc reconstructions indicated that Hmx3-derived Htr3a-GFP+ cells exhibited the molecular, electrophysiological and morphological profile of NGCs. Taken together, these results demonstrate that cortical NGCs have a precise developmental trajectory that is linked to the expression of the transcription factor (TF) Hmx3 in a discrete embryonic subpallial region.

To determine whether the POA could contribute to Htr3a-GFP INs, we crossed Htr3a-GFP; R26R-tdTOM^fl/fl mice with Hmx3-Cre mice, a reporter line previously shown to fate map a population of cortical INs derived from cells located in the POA (Gelman et al., 2009). Examination of brains from Hmx3-Cre::Htr3a-GFP; R26R-tdTOM^fl/fl matings at embryonic age 14.5 (E14.5) revealed a large fraction of Hmx3; tdTOM+ cells co-labelled with Htr3a-GFP (85.2 ± 0.9%; 1675/1986 cells in the overlap zone) in a restricted region of the POA, located ventrally to the anterior commissure (Figure 1A,C, Figure 1—source data 1). Individual co-labelled Hmx3; tdTOM+/Htr3a-GFP+ cells displaying migratory profiles were observed at more caudal levels entering the CGE (Figure 1B), suggesting that a fraction of Hmx3; tdTOM+/Htr3a-GFP+ cells migrate from the POA into the CGE. In situ hybridization indicated that the vast majority (95.8 ± 0.9%; 115/120 cells) of Hmx3; tdTOM+/Htr3a-GFP+ cells located in the POA expressed the endogenous Htr3a mRNA, in contrast to Hmx3; tdTOM+cells negative for Htr3a-GFP (0.5 ± 0.5%; 1/158 cells) (Figure 1D, Figure 1—source data 1). In addition, a large fraction of Hmx3; tdTOM+/Htr3a-GFP+ cells in the POA expressed the TFs PROX1 (54.0 ± 2.2%; 249/463 cells) and NR2F2 (65.9 ± 1.3%; 795/1212 cells), which have previously been shown to be enriched in CGE-derived INs (Cai et al., 2013; Ma et al., 2012; Miyoshi et al., 2015; Rubin and Kessaris, 2013), but more rarely the TF NKX2.1 (15.3 ± 1%; 175/1146 cells) (Figure 1E,F, Figure 1—source data 1). Collectively, these results indicate that a fraction of Hmx3+ cells located in the POA express the 5-HT_3AR and a pattern of TFs related to CGE-derived INs.

Figure 1

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Figure 1—source data 1

Detailed counts of cells quantified in Figure 1 in the different experimental conditions.

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To determine whether Hmx3; tdTOM+/Htr3a-GFP+ cells in the POA eventually give rise to a specific subpopulation of cortical INs, we examined brains at various postnatal ages. From P5 to P21, Hmx3; tdTOM+/Htr3a-GFP+ INs were found distributed preferentially in superficial cortical layers and in a variety of other brain regions including in the hippocampus (Figure 2A, Figure 2—figure supplement 1). Hmx3; tdTOM+/Htr3a-GFP+ cells were rarely observed at postnatal ages in the subpallial brain regions corresponding to the embryonic POA (i.e., the preoptic nuclei) (Figure 2—figure supplement 2). In situ hybridization for Htr3a mRNA indicated that Hmx3; tdTOM+/Htr3a-GFP+ cells expressed the Htr3a transcript, similarly to Htr3a-GFP+ cells negative for Hmx3; tdTOM (Figure 2C). About half (51.9 ± 2.1%; 863/1653 cells) of Hmx3-derived cells in the cortex were co-labelled with Htr3a-GFP+ and virtually all Hmx3; tdTOM+/Htr3a-GFP+ (96.1 ± 0.5%; 357/372 cells) were positive for the neuronal marker NeuN (Figure 2D,E, Figure 2—source data 1). In contrast, the fraction of Hmx3; tdTOM+ cells negative for Htr3a-GFP mostly did not express NeuN (3.4 ± 1.3%; 28/758 cells) (Figure 2D,E, Figure 2—source data 1), and remained relatively constant across postnatal ages (Figure 2—figure supplement 3A, Figure 2—figure Supplement 3—source data 1). These cells displayed the morphology of glial cells and expressed the astrocytic markers GFAP and S100β as well as the oligodendrocytic marker SOX10 (Figure 2—figure supplement 3B–D). Overall, these findings indicate that the cortical Hmx3-derived lineage observed in the POA differentiate into INs that are Htr3a-GFP+, glial cells that are Htr3a-GFP negative and, for a small fraction, to NeuN+ neurons negative for Htr3a-GFP.

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Detailed counts of cells quantified in Figure 2 in the different experimental conditions.

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A second distinct region in the POA expressing Dbx1 was previously reported to give rise to subsets of cortical INs (Gelman et al., 2011). To determine whether a fraction of Htr3a-GFP+ INs also originate from Dbx1-expressing cells, we examined Dbx1-Cre::Htr3a-GFP; R26R-tdTOM^fl/fl brains at postnatal periods. While the overall contribution of Hmx3-derived cells to the Htr3a-GFP IN population in the cortex increased with postnatal maturation from P5 (6.8 ± 0.2%; 77/1118 cells) to P21 (16.0 ± 0.3%; 863/5405 cells) (Figure 3A,C), only minimal fractions (1.44 ± 0.2%; 81/5741 cells at P5; 0.8 ± 0.2%; 20/2551 cells at P21) of Htr3a-GFP+ INs were fate-mapped with Dbx1; tdTOM (Figure 3B,C, Figure 3—source data 1). Moreover, Dbx1; tdTOM+ cells were preferentially found in deep cortical layers and expressed the MGE-enriched TF SOX6 (30.4 ± 2.2%; 82/266 cells), while PROX1 was found only in a very small fraction of Dbx1; tdTOM+ cells expressing also the Htr3a-GFP (2.2 ± 0.7%; 6/266 cells) (Figure 3D, Figure 3—source data 1). In addition, Dbx1; tdTOM+ INs expressed Lhx6 mRNA (Figure 3E), and the MGE-related markers SST and PV (Figure 3—figure supplement 1), and only very rarely the Htr3a mRNA (Figure 3F). Overall, these results indicate that Hmx3-derived 5-HT_3AR+ cortical INs largely originate from Hmx3-expressing cells but not from the Dbx1+ domain, which gives rise to INs expressing MGE-related markers.

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Detailed counts of cells quantified in Figure 3 in the different experimental conditions.

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We next examined whether Hmx3; tdTOM+/Htr3a-GFP+ cells expressed distinct patterns of TFs involved in cortical IN subtype specification. At P21, we found that, similarly to Htr3a-GFP+ INs, a large fraction (65.8 ± 3.4%; 202/308 cells) of Hmx3; tdTOM+/Htr3a-GFP+ INs expressed the CGE-enriched but not the MGE-related TFs. Indeed, a large fraction of them (65.8 ± 3.4%; 202/308 cells) expressed PROX1 but not SOX6 (Figure 4A,B, Figure 4—source data 1), as well as NR2F2 (32.7 ± 5.9%; 71/218 cells), SP8 (9.8 ± 2.6%; 22/218 cells), and both SP8 and NR2F2 (8.8 ± 2.0%; 18/218 cells) (Figure 4C,D, Figure 4—source data 1). The fraction of Hmx3; tdTOM+/Htr3a-GFP+ expressing at least one of these two latter TFs was smaller and biased toward NR2F2 expression, when compared to Htr3a-GFP+ INs (Figure 4D, Figure 4—figure supplement 1, Figure 4—source data 1). These findings indicate that Hmx3; tdTOM+/Htr3a-GFP+ cortical INs express a repertoire of TFs related to CGE but not to MGE-derived INs.

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Detailed counts of cells quantified in Figure 4 in the different experimental conditions.

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We next examined whether Hmx3; tdTOM+/Htr3a-GFP+ INs expressed classical CGE markers such as reelin, NPY and VIP (Lee et al., 2010; Murthy et al., 2014; Vucurovic et al., 2010). Quantification across layers revealed that a large fraction of Hmx3; tdTOM+/Htr3a-GFP+ INs expressed reelin or NPY. This was particularly striking in layer 1 (L1) for reelin (Figure 5A,C) and in L2–6 for NPY (Figure 5B,E), respectively (Figure 5—source data 1). Overall, Hmx3; tdTOM+/Htr3a-GFP+ INs accounted for approximately a third of all reelin+/Htr3a-GFP+ INs (34.5 ± 2.3%; 267/797 cells) and of all NPY+/Htr3a-GFP+ INs (27.7 ± 2.3%; 149/571 cells) (Figure 5D,F, Figure 5—source data 1). Given that INs expressing reelin have been shown to co-express NPY (Lee et al., 2010), we assessed reelin and NPY co-expression in Hmx3; tdTOM+/Htr3a-GFP+ cells. At P21, only a small fraction (8.0 ± 0.9%; 17/232 cells) of these cells expressed NPY without reelin, thus indicating that reelin labels the largest fraction (66.1 ± 8.6%; 267/398 cells) of Hmx3-derived Htr3a-GFP+ INs (Figure 5G,H, Figure 5—source data 1). In contrast, Hmx3; tdTOM+/Htr3a-GFP+ INs did not co-label nor with the CGE-specific marker VIP (Figure 5I) neither with the MGE-enriched markers SST and PV (Figure 5—figure supplement 1). These results indicate that Hmx3-derived Htr3a-GFP+ INs mainly belong to the reelin but not to the VIP subtypes and account for an important fraction of all reelin+/Htr3a-GFP+ INs.

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Detailed counts of cells quantified in Figure 5 in the different experimental conditions.

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Two distinct profiles of reelin-expressing INs have been identified in L1 of the neocortex, namely neurogliaform (NGCs) and single bouquet-like cells (SBCs) (Cadwell et al., 2016; Jiang et al., 2015). At a molecular level, NGCs are strongly enriched in the carbonic anhydrase 4 (Car4) transcript in contrast to SBCs (Cadwell et al., 2016). Using single-molecule fluorescent in situ hybridization experiments (Wang et al., 2012), we found that Hmx3; tdTOM+/Htr3a-GFP+ INs in L1 exhibited significantly higher levels of Car4 transcripts in contrast to Htr3a-GFP+ INs (Figure 6A, Figure 6—source data 1), thus indicating that Hmx3-derived Htr3a-GFP+ INs share the molecular profile of NGC. To further verify whether their morphological and electrophysiological features could fit with NGCs, we performed whole-cell recordings (Figure 6B) and reconstructions (Figure 6C,D; Figure 6—figure supplement 1) of Hmx3-derived versus non Hmx3-derived Htr3a-GFP+ INs in L1 of the barrel cortex. There, Hmx3; tdTOM+/Htr3a-GFP+ INs displayed the characteristic morphology of elongated NGCs with dense axonal ramifications mostly restricted to L1 (Figure 6C, Figure 6—figure supplement 1), whereas Htr3a-GFP+ INs negative for tdTOM had the morphology of SBCs with less developed axonal processes that extended deeper in cortical layers (Figure 6D). With regard to their first action potential (AP) at rheobase, NGCs are reported to display a type 1 profile with only an after-hyperpolarization potential (AHP), whereas SBCs show a type 2 profile consisting of an AHP followed by an after-depolarization potential (ADP) (Cadwell et al., 2016; Jiang et al., 2015). Strikingly, all (29 out of 29) recorded Hmx3; tdTOM+/Htr3a-GFP+ INs were of type 1, thus confirming their NGC identity. Moreover, the vast majority of them (23 out of 29) were of type 1A with a deep and wide AHP and only a few (6 out of 29) were of type 1B with a shallow and narrow AHP (Figure 6E, left, Figure 6—source data 2). Htr3a-GFP+ INs negative for Hmx3; tdTOM had more variable profiles, but the majority of them (24 out of 28) were displaying a type two profile with an average ADP amplitude of 2.30 ± 0.51 mV, suggesting that they were SBCs. Most of them (20 out of 28) were of type 2B with a small ADP below the spike threshold, a few others (4 out of 28) were of type 2A with a big ADP above the spike threshold (Figure 6E, right, Figure 6—source data 2) and another few of them (4 out of 28) had not measurable ADP (not shown). Hmx3; tdTOM+/Htr3a-GFP+ INs showed also a higher tendency to late-spiking when compared to Htr3a-GFP+ INs (Figure 6F, Figure 6—source data 2). Hmx3; tdTOM+/Htr3a-GFP+ INs had bigger AP delay average, but not significantly different from Htr3a-GFP+ INs negative for Hmx3; tdTOM (Figure 6—figure supplement 2C, Figure 6—source data 2). However, the variability of individual cell values was higher for Hmx3; tdTOM+/Htr3a-GFP+ INs, indicating that these cells tend to be more late-spiking, a characteristic of NGCs (Cadwell et al., 2016; Jiang et al., 2015). Alignement of the first APs at rheobase revealed other putative differences between the two groups (Figure 6G, Figure 6—source data 2). After quantification, Hmx3; tdTOM+/Htr3a-GFP+ INs significantly differed from Htr3a-GFP+ INs negative for Hmx3; tdTOM in the first AP amplitude (Peak), AHP amplitude (AHP), membrane resistance (Rm) (Figure 6H, Figure 6—source data 2) and threshold potential (Vthr) (Figure 6—figure supplement 2C). We next aimed to determine whether Hmx3 and non Hmx3-derived Htr3a-GFP+ INs classes in L1 could be predicted from single-cell electrophysiological properties. Using an automatic cell type classifier based on combined electrophysiological measures, we were able to predict the Hmx3-derived class with 80.7% accuracy, with highest weights found on ADP, Peak and AHP but not Vthr (Figure 6I,J; Figure 6—figure supplement 2A,B, Figure 6—source data 2). Finally, we analysed Hmx3; tdTOM+/Htr3a-GFP+ INs in other cortical layers to determine whether they displayed the same NGC characteristics. Similarly to L1 cells, Car4 expression in L2-6 was significantly higher in Hmx3; tdTOM+/Htr3a-GFP+ INs as compared to Htr3a-GFP+ INs negative for tdTOM (Figure 6—figure supplement 3A,B, Figure 6—source data 1). Morphological recovery of Hmx3; tdTOM+/Htr3a-GFP+ INs located in L2–6 revealed that all cells (7 out of 7) had also the characteristic morphology of NGCs (Figure 6—figure supplement 4). Furthermore, characteristic properties of NGC like the tendency to late spiking, the depth of AHP, and the level of Vthr were significantly more pronounced in these cells compared to L1 cells (Figure 6—figure supplement 3C,E). Overall, these data indicate that Htr3a-GFP+ INs displaying the molecular, morphological and electrophysiological properties of NGC INs originate from Hmx3-expressing cells in the embryonic POA (Figure 7, orange), whereas SBCs in layer 1, as well as VIP +INs, are more likely to originate from the CGE (Figure 7, green).

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Detailed counts of cells expressing Car4 quantified in Figure 6 in the different experimental conditions.

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Figure 6—source data 2

Electrophysiological properties of cells quantified in Figure 6.

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Figure 7

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Distinct subtypes of local GABAergic INs are required to regulate microcircuit function (Cardin et al., 2009; Fu et al., 2014; Kepecs and Fishell, 2014; Pfeffer et al., 2013; Pi et al., 2013; Pinto and Dan, 2015; Sohal et al., 2009; Zhang et al., 2014). Whether current classifications of cortical IN subtypes relate to intrinsic biological processes such as their developmental specification is a key question in the field (Huang, 2014; Taniguchi et al., 2013). Among cortical INs, NGCs are considered as belonging to a distinct subtype acting as a main effector of a powerful inhibitory motif recruited by long-range connections (Tamás et al., 2003; Craig and McBain, 2014; Palmer et al., 2012). Here we aimed to track the developmental trajectory of NGCs using genetic fate mapping strategies. We find that NGCs derive from Htr3a-GFP+/Hmx3+ cells located in the embryonic POA, but not from Dbx1+ cells. Strikingly, L1 Hmx3-derived Htr3a-GFP+ INs display the distinct molecular, morphological and electrophysiological properties of NGCs, whereas Htr3a-GFP+ INs negative for Hmx3 have the profile of SBCs (Cadwell et al., 2016). Hmx3-derived Htr3a-GFP+ NGCs represent about a third of reelin-expressing Htr3a-GFP+ INs. At a molecular level, Hmx3; tdTOM+/Htr3a-GFP+ NGCs express CGE-related TFs such as NR2F2 and PROX1, indicating that they share common features with CGE-derived INs. Overall, these results indicate that cortical NGCs derive from a discrete embryonic area located in the subpallial POA and that their specification is linked to the expression of the TF Hmx3.

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Author details

1. Mathieu Niquille

   1. Department of Psychiatry, University of Geneva, Geneva, Switzerland
   2. Department of Basic Neuroscience, University of Geneva, Geneva, Switzerland

   Contribution

   Data curation, Formal analysis, Investigation, Writing—review and editing

   Contributed equally with

   Greta Limoni and Foivos Markopoulos

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0002-2860-3861

2. Greta Limoni

   1. Department of Psychiatry, University of Geneva, Geneva, Switzerland
   2. Department of Basic Neuroscience, University of Geneva, Geneva, Switzerland

   Contribution

   Data curation, Formal analysis, Investigation, Writing—review and editing

   Contributed equally with

   Mathieu Niquille and Foivos Markopoulos

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0002-6808-9510

3. Foivos Markopoulos

   Department of Basic Neuroscience, University of Geneva, Geneva, Switzerland

   Contribution

   Data curation, Formal analysis, Investigation, Writing—review and editing

   Contributed equally with

   Mathieu Niquille and Greta Limoni

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0002-5501-9249

4. Christelle Cadilhac

   1. Department of Psychiatry, University of Geneva, Geneva, Switzerland
   2. Department of Basic Neuroscience, University of Geneva, Geneva, Switzerland

   Contribution

   Supervision, Funding acquisition, Validation, Methodology, Writing—review and editing

   Competing interests

   No competing interests declared

5. Julien Prados

   1. Department of Psychiatry, University of Geneva, Geneva, Switzerland
   2. Department of Basic Neuroscience, University of Geneva, Geneva, Switzerland

   Contribution

   Conceptualization, Supervision, Funding acquisition, Validation, Investigation, Methodology, Writing—original draft, Administration, Writing—review and editing

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0002-8546-241X

6. Anthony Holtmaat

   Department of Basic Neuroscience, University of Geneva, Geneva, Switzerland

   Contribution

   Formal analysis, Investigation, Writing—review and editing

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0002-7577-0769

7. Alexandre Dayer

   1. Department of Psychiatry, University of Geneva, Geneva, Switzerland
   2. Department of Basic Neuroscience, University of Geneva, Geneva, Switzerland

   Contribution

   Data curation, Formal analysis, Writing—review and editing

   For correspondence

   alexandre.dayer@unige.ch

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0002-4490-9780

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