Embryonic interneurons from the medial, but not the ... - Springer Link

Brain Struct Funct (2017) 222:539–547 DOI 10.1007/s00429-016-1232-y

ORIGINAL ARTICLE

Embryonic interneurons from the medial, but not the caudal ganglionic eminence trigger ocular dominance plasticity in adult mice Marcel Isstas1 • Manuel Teichert1 • Ju¨rgen Bolz1 • Konrad Lehmann1

Received: 24 August 2015 / Accepted: 28 April 2016 / Published online: 10 May 2016 Ó Springer-Verlag Berlin Heidelberg 2016

Abstract The maturation of cortical inhibition provided by parvalbumin-containing basket cells derived from the medial ganglionic eminence (MGE) is a key event in starting the enhanced visual cortical plasticity during the critical period. Although it is generally assumed that a further increase in inhibition closes the critical period again, it was recently shown that embryonic interneurons derived from the MGE can induce an additional, artificial critical period when injected into the visual cortex of young mice. It has, however, remained open whether this effect was indeed specific for MGE-derived cells, and whether critical period-like plasticity could also be induced in fully adult animals. To clarify these issues, we injected explants from either the MGE or the caudal ganglionic eminence (CGE) into the visual cortices of fully adult mice, and performed monocular deprivation 33 days later for 4 days. Animals implanted with MGE cells, but not with CGE cells, showed marked ocular dominance plasticity. Immunohistochemistry confirmed that the injected cells from both sources migrated far in the host cortex, that most developed into neurons producing GABA, and that only cells from the MGE expressed parvalbumin. Thus, our results confirm that the plasticity-inducing effect of embryonic interneurons is specific for cells from the MGE, and is independent of the host animal’s age.

J. Bolz and K. Lehmann contributed equally. & Konrad Lehmann [email protected] 1

Institut fu¨r Allgemeine Zoologie and Tierphysiologie, Friedrich Schiller-Universita¨t Jena, Jena, Germany

Keywords Visual cortex Ocular dominance plasticity Inhibitory interneurons Ganglionic eminences

Introduction Cortical large basket cells expressing parvalbumin (PV) exert a far-ranging influence on neuronal processing. In addition to regulating sensory computation (Atallah et al. 2012; Lee et al. 2012; Wilson et al. 2012) on a short-term basis, they have notably been shown to trigger the critical period for ocular dominance plasticity in the binocular visual cortex by providing an increasing level of inhibition during their maturation (Fagiolini and Hensch 2000; Hensch et al. 1998; Sugiyama et al. 2008). Remarkably, PV-containing basket cells appear to induce plasticity single-handedly, because transplantation of newborn inhibitory cells from the medial ganglionic eminence (MGE), a sizeable proportion of which are destined to become PV basket cells, into the postnatal mouse brain has been shown to induce an artificial critical period of ocular dominance plasticity (Southwell et al. 2010). However, the animals in that study were still very young when ocular dominance plasticity was challenged by monocular deprivation (MD), i.e., approximately 35 and 45 days. At this age, there is still some remnant plasticity in the visual cortex, which only disappears completely when mice have reached full adulthood at 100 days of age (Lehmann and Lo¨wel 2008). The mechanisms that start to restrict plasticity after the critical period are still incompletely understood, but further increased inhibition, possibly recruited by nicotinic signaling (Morishita et al. 2010), may play a role. Indeed, interventions that decrease cortical GABA release reinstate plasticity in adult rodents (Hanover et al. 1999; Harauzov et al. 2010; Huang et al. 1999; Maya Vetencourt et al. 2008, 2011).

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Against this backdrop, it is an important question whether PV-containing basket cells also have the power to induce ocular dominance plasticity in fully adult mice. Davis and colleagues have recently shown that plasticity induced by a transplantation of MGE cells into the adult mouse visual cortex could be used to rescue amblyopia (Davis et al. 2015). If confirmed, that would signify that additional inhibitory interneurons bypass all plasticitylimiting mechanisms, which could therefore be assumed to act through the intrinsic interneurons. Additionally, it is important to check whether the capacity to trigger enhanced plasticity is indeed restricted to cells derived from the medial ganglionic eminence (MGE). While the MGE is the source of PV-expressing basket cells, it cannot be excluded a priori that other kinds of interneurons might have the same effect. Indeed, a recent study has shown that somatostatin-containing interneurons, which are also produced in the MGE, can likewise induce critical period-like plasticity (Tang et al. 2014). The caudal ganglionic eminence (CGE) and the preoptic area (POA) have, in recent years, both been shown to produce separate, biochemically, functionally, and morphologically distinct populations of interneurons (Gelman et al. 2009; Miyoshi et al. 2010; Xu et al. 2004), raising the question whether these cells can modulate visual cortical plasticity, too. In the present paper, we, therefore, injected explants from all embryonic structures containing future GABAergic interneurons into the visual cortex of fully adult ([PD110) male mice. Explants from the POA and the lateral ganglionic eminence survived in the host cortex, but did not produce migrating cells that could settle down into the cortical network. Cells from the MGE and CGE, in contrast, migrated far in the host cortex and developed a mature phenotype. Probing ocular dominance plasticity in animals that had received MGE or CGE explants showed that only MGE-derived cells are able to induce enhanced ocular dominance plasticity in fully adult mice. Results of the present paper have been presented before in abstract form (Lehmann et al. 2014).

Materials and methods Animals and housing conditions Male C57BL/6 mice older than postnatal day (PD) 110 at transplantation were reared in standard housing conditions, i.e., in sibling groups kept in Makrolon cages. After transplantation, the animals were separated into single cages. During the optical imaging experiments, the animals’ age was between PD146 and PD330 (median: PD180, mean: PD 209).

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Donor mice carried the EGFP gene under a b-actin promoter on a C57BL/6 background. Throughout the experiments, food and water were provided ad libitum. All experimental procedures were performed according to the German Law on the Protection of Animals and the corresponding European Communities Council Directive of November 24, 1986 (86/609/EEC), and were approved by the Thu¨ringer Landesamt fu¨r Lebensmittelsicherheit und Verbraucherschutz (Thuringia State Office for Food Safety and Consumer Protection) under the registration number 02-027/11. Preparation and transplantation of explants from embryonic brains Timed-pregnant EGFP mice at embryonic day 14 were terminally anesthetized with 1 ml i.p. 10 % chloral hydrate, the uteri were dissected and the embryos removed under sterile conditions. The brains were dissected in Gey’s balanced salt solution containing glucose (GBSS/Glc). Medial and caudal ganglionic eminences were punched out from opened and flattened hemispheres and divided into equal parts. For the MGE, care was taken to include ventral and lateral aspects in each chunk, since they appear to differ in their production of parvalbumin- and somatostatin-containing interneurons (Inan et al. 2012; Wonders et al. 2008). The POA was punched from 250 lm frontal slices prepared with a tissue chopper. The explants were stored in ice-cold medium (neurobasal medium with 2 % B27 supplement and 1.3 % glucose) until transplantation. Host mice were anesthetized with 3 % isoflurane in 50 % oxygen and 50 % nitrous oxide. During the operation, the narcosis was maintained by 1.5 % isoflurane in the same gaseous mixture, applied via a nose tube. Dexamethasone (0.05 ml s.c. of 4 mg/ml) was applied to prevent inflammation and cortical oedema, and carprofen (0.02 ml s.c. of 10 % solution) was given as an analgesic. Additionally, xylocaine gel was daubed on the skin for local anesthesia. The scalp was opened and retracted, and three trepanations were made around the binocular visual cortex (first: 3.4 mm lateral and 1.8 mm anterior from lambda, second: 2.7 mm lateral and 0.9 mm anterior, third: 4.1 mm lateral and 0.9 mm anterior), using a 0.2 mm dental drill. The explants were frontally loaded into beveled glass micropipettes and injected by air pressure at a depth of 0.8 mm. Afterward, the scalp was sutured, and the wound was treated and checked daily. Monocular deprivation For probing visual cortical plasticity, we monocularly deprived mice for 4 days according to published protocols (Gordon and Stryker 1996; Lehmann et al. 2012). In all


cases, the right eyes were sutured shut. Animals were checked daily to make sure that the eyes remained closed; animals in which the eye was not completely closed were excluded from the experiments. Optical imaging Using the imaging method of temporally encoded maps (Kalatsky and Stryker 2003), visual cortical responses in the left hemisphere were recorded as described previously (Lehmann and Lo¨wel 2008; Lehmann et al. 2012; Yeritsyan et al. 2012) under halothane (1 % in 1:1 O2/N2O) anesthesia, supplemented by chlorprothixene (0.2 mg/mouse, i.m.), atropine (0.3 mg/mouse, s.c.), and dexamethasone (0.2 mg/mouse, s.c.). With a 135 mm 9 50 mm tandem lens configuration (Nikon, Inc., Melville, NY), we recorded optical images of intrinsic signals in a cortical area of 4.6 9 4.6 mm2 at a wavelength of 610 ± 3 nm. Horizontal drifting bars (2° wide), spaced 80° apart, were presented at a temporal frequency of 0.125 Hz in the binocular visual field of the recorded left hemisphere (-5° to ?15° azimuth) in front of the animal. Visual stimuli were presented alternately to the left and right eye. Ocular dominance indices (ODIs) were calculated from activity maps as described previously (Cang et al. 2005; Lehmann and Lo¨wel 2008). Briefly, within a region of interest, all pixels above a threshold at 30 % of peak amplitude were used, and OD was calculated for each pixel as (contra - ipsi)/(contra ? ipsi), and averaged across all selected pixels. At least three ODIs per animal were obtained and averaged; experiments with less than three ODIs were discarded.

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perfused with 0.1 M PBS, followed by 4 % PFA in PBS. The brains were dissected, postfixed, cryoprotected, and frozen at -80 °C. Sections of 16 lm (synaptophysin-staining) or 25 lm were taken on a cryostat (Leica) and stained for GFP (rabbit-anti-GFP, 1:1000, Life technologies, or goat-antiGFP, Rockland Inc.), VIP (rabbit-anti-VIP, 1:300, Immunostar), PV (rabbit-anti-PV, 1:3000, Abcam), GABA (rabbit-anti-GABA, 1:1000, Sigma), calretinin (rabbit-anticalretinin, 1:300, Swant), calbindin (rabbit-anti-calbindin, 1:1000, Sigma), somatostatin (goat-anti-somatostatin, 1:300, Santa Cruz Biotechnology), and synaptophysin (mouse-anti-synaptophysin, 1:200, Millipore). As secondary antibodies, we used Dylight 488 and Cy3 from donkey, both anti-rabbit and anti-goat (Jackson ImmunoResearch). The sections were observed and documented on a laser scanning microscope (Zeiss LSM-510) and analyzed using ImageJ. Statistical analysis The optical imaging data were analyzed by two-way ANOVA, followed by post hoc testing using t tests with Bonferroni correction. Levels of significance were set at: *p \ 0.05; **p \ 0.01; ***p \ 0.001.

Results Cells from MGE and CGE, but not LGE and POA explants migrate into the adult cortex

After the optical imaging experiment, the animals were deeply anesthetized by chloral hydrate and transcardially

We injected explants from the medial (MGE), caudal (CGE), and lateral (LGE) ganglionic eminences, as well as the preoptic area (POA), of EGFP? embryos into the visual cortices of fully adult male mice ([PD146). Cells from all explants survived in the host cortex, and in no case was the formation of a tumor observed. Histological verification (Fig. 1a, b) and optical imaging of retinotopic

Fig. 1 Transplanted cells are able to reach the binocular visual cortex. a, b Frontal slices through the left visual cortex of animals injected with explants from the MGE and CGE are shown. Green transplanted cells; blue DAPI. Transplanted cells migrated into the

visual cortex. c Optical imaging of intrinsic signals confirmed that the stereotaxic positions chosen for transplantation were narrowly surrounding the binocular portion of the visual cortex. MGE, CGE medial/caudal ganglionic eminence. Scale bars are 1 mm

Immunohistochemistry

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33.4 % in layer V, whereas only 1.8 and 10.3 % were found in layers II/III and IV, respectively. CGE cells (Fig. 2f) never reached the supragranular layers, but were almost exclusively found in layers V (18.8 %) and VI (80.3 %). MGE and CGE explants give rise to complementary interneuron populations

Fig. 2 Cells from MGE and CGE, but not LGE and POA explants migrate into the host cortex. Typical injections are shown. While many migrating cells can be seen in cortices having received MGE (a) or CGE (b) explants, LGE (c) and POA (d) explants are sharply bordered, although they extend neurites into the surrounding tissue. Dotted lines indicate the cortical boundaries. Migrating cells from the MGE (e) and CGE (f) preferentially settle down in deep cortical layers. MGE, CGE, LGE medial/caudal/lateral ganglionic eminence, POA preoptic area. Scale bar is 500 lm and refers to all images

maps (Fig. 1c) confirmed that the positions of the transplantation were narrowly flanking the binocular visual cortex. All transplanted MGEs (n = 14) gave rise to migrating neurons (Fig. 2a), as did all transplanted CGEs (n = 6, Fig. 2b). In contrast, out of three transplanted LGEs (Fig. 2c) and two POAs (Fig. 2d), not a single one produced migrating neurons. However, the cells in the transplanted LGEs and POAs survived for at least 30 days, and extended axons and dendrites into the surrounding tissue, and even into the contralateral hemisphere. Cells from the MGE were found at distances of up to 1.3 ± 0.1 mm from the injection site, CGE cells even at 2.4 ± 0.2 mm maximal distance. Both populations of transplanted cells settled preferentially in deep cortical layers. Of MGE cells (Fig. 2e), 54.4 % came to reside in layer VI and

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At 30 DAT, the cells derived from the MGE and CGE explants had acquired a mature neuronal morphology, and migrating cells were no longer found. To check whether the cells were integrated into the intrinsic neuronal circuits, we performed double-staining for GFP and synaptophysin. Confocal microscopy showed that on both MGE- and CGE-derived cells, labelled boutons were reliably found in close apposition to GFP-stained transplanted cells (Fig. 3a, i). All transplanted cells appeared in a large variety of cell morphologies, but MGE-derived cells were often recognizable as large basket cells (Fig. 3b, c), whereas typical double bouquet cells were found around CGE explants (Fig. 3j, k). To further characterize the resulting cell types, we performed a double-staining for the most common markers of GABAergic cell subtypes (Fig. 3e–h, m–p). Of the transplanted MGE cells, 93 % were double-stained for GABA, 24 % expressed calbindin, 45 % somatostatin, and 13 % parvalbumin, while only 9 % expressed vasointestinal peptide (VIP) which is typical for CGE-derived interneurons (Fig. 3d). Of CGE-derived cells, in turn, 73 % stained for GABA, 11 % for calbindin, 50 % for VIP, and 32 % for calretinin, whereas we found only one neuron (0.6 %) expressing parvalbumin (Fig. 3l). MGE, but not CGE explants induce plasticity in fully adult mice Having shown that both MGE and CGE give rise to GABAergic neurons when transplanted into the fully adult mouse cortex, we investigated whether these cells were also capable of inducing ocular dominance plasticity in mice of that age. We, therefore, performed a monocular deprivation (MD) at 35 DAT, and used optical imaging of intrinsic signals to measure ocular dominance 4 days later. Representative maps obtained after 4 days of MD from animals injected with vehicle, MGE or CGE explants are shown in Fig. 4a. Maps from all animals displayed clear retinotopic arrangement and an activity that was standing out from the background. As expected, the injection of vehicle did not induce plasticity. The control ODI of vehicle-injected animals was 0.25 ± 0.04 (n = 5) and did not change significantly after MD (0.22 ± 0.02, n = 5, Fig. 4b). In MGEinjected animals, however, 4 days of MD reduced the ODI significantly (p \ 0.05, Bonferroni-corrected t test) from 0.18 ± 0.01 (n = 5) to 0.05 ± 0.03 (n = 8). This latter


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Fig. 3 Cells from MGE and CGE explants give rise to complementary interneuron populations. a, i Double-staining for GFP (green) and synaptophysin (red) shows that transplanted MGE (a) and CGE (i)derived cells receive synaptic input (yellow). b, c Representative single cells from transplanted MGEs. d, l Percentages of EGFP positive cells from the MGE (d) and CGE (l) double-stained for

interneuronal markers are given. CB calbindin, SST somatostatin, PV parvalbumin, VIP vasointestinal peptide, CR calretinin. e–h Doublestaining of MGE-derived cells (green) with interneuronal markers (red). j, k Representative single cells from transplanted CGEs. m– p Double-staining of CGE-derived cells (green) with interneuronal markers (red). Scale bars are 50 lm

value was also significantly different (p \ 0.01) from vehicle-injected animals with MD. The change in ODI was achieved by a reduction in deprived-eye activity [control: 1.93 ± 0.46 (910-4), MD: 1.56 ± 0.22 (910-4)], that was, however, not significant (p = 0.5, t test). There was no change in open-eye activity [control: 1.47 ± 0.38 (910-4), MD: 1.45 ± 0.15 (910-4), p = 0.96]. Transplantation of CGE, in contrast, had no effect on cortical plasticity. After MD, the ODI changed non-significantly from 0.21 ± 0.03 (n = 3) to 0.24 ± 0.03 (n = 3), and there was a highly significant difference between MGE-

and CGE-injected MD animals (p \ 0.01, Bonferroni-corrected t test). These data show that only MGE-derived cells, but not cells from the CGE, are able to induce ocular dominance plasticity in the fully adult visual cortex.

Discussion We have shown in this study that explants of the MGE and CGE, but not LGE and POA, give rise to migrating interneurons when transplanted into the fully adult visual

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Fig. 4 Only cells from the MGE induce ocular dominance plasticity in adult mice. a Representative retinotopic maps from monocularly deprived animals injected with vehicle, MGE- and CGE-explants are displayed. In each panel, retinotopic phase-maps (top) and grayscale amplitude maps (center row) elicited by contralateral (left) and ipsilateral (right) eye stimulation are shown. In the bottom row, colorcoded ocular dominance maps represent contralateral bias in warm colors and ipsilateral dominance in cool colors. Histograms show the ocular dominance distribution of all pixels in the area of interest. b Ocular dominance indices (ODI) are shown for animals having received explants from the MGE or CGE, or vehicle, into the left visual cortex. Each symbol represents one animal

cortex, and that these cells attain the characteristics of mature GABAergic interneurons. Moreover, cells from the MGE, but not from the CGE, were able to induce ocular dominance plasticity at 35 days after transplantation, allowing for a shift in ocular dominance after 4 days of monocular deprivation. The adult cortex can still accommodate transplanted interneurons The striking capacity of the postnatal mouse brain to incorporate transplanted embryonal interneurons has been studied a lot in recent years [see (Southwell et al. 2014) for review]. It has been shown that transplanted MGE cells

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migrate and survive in the brains of young adult mice at 2–3 months of age (Wichterle et al. 1999), and assume mature interneuronal morphologies, biochemical markers, firing properties, and connections (Alvarez-Dolado et al. 2006). When injected into the neonatal mouse brain, MGE cells differentiate into functional interneurons within 30 days, and cells that have survived so far survive at least for another 60 days (Alvarez-Dolado et al. 2006). We confirm and extend these findings showing survival of transplanted MGE cells in the fully adult mouse cortex (i.e., beyond PD100) for at least 210 DAT, and demonstrating that CGE-derived cells, too, can settle down in the adult brain. It was already known that cells from the LGE, which do not normally populate the cortex, do not migrate when transplanted into the adult cortex (Wichterle et al. 1999). Instead, they are able to contribute cells to the rostral migratory stream when transplanted into the ventricular border. In contrast, the failure of POA-derived cells to migrate into the cortex was surprising. The POA gives rise to a separate set of cortical interneurons (Gelman et al. 2009), which may rely on different guidance cues than cells from the MGE and CGE (Rudolph et al. 2014; Zimmer et al. 2011). Until now, research has focused on the behavior and effects of transplanted MGE cells (Alvarez-Dolado et al. 2006; Martinez-Cerdeno et al. 2010; Southwell et al. 2012). We here show that interneurons from the embryonal CGE, too, migrate far in the host cortex and acquire mature morphologies and interneuronal markers. Our results confirm that CGE-derived cells form a separate population that is biochemically distinct from MGE-derived cells: whereas cells from the MGE are characterized by the expression of parvalbumin and somatostatin, many CGE-derived interneurons contain VIP and calretinin, but not parvalbumin. The possibility to transplant these clearly segregated groups of cells into a host brain will enable further studies on the capacities and network effect of different interneuron types. Transplantation of MGE induces ocular dominance plasticity in the adult mouse brain After its peak during the critical period, ocular dominance plasticity declines during adolescence and is completely absent in fully adult animals (Blakemore et al. 1978; Daw et al. 1992; Fagiolini et al. 1994; Lehmann and Lo¨wel 2008). The fact that we could still induce plasticity in mice of that age by the transplantation of MGE cells is, therefore, a highly relevant observation. It shows that additional interneurons are able to release the brake on plasticity even far beyond the critical period. The mechanisms by which this is achieved remain to be determined. So far, it has been


shown that plasticity after the critical period can be limited both by the increased expression of Lynx1, an enhancer of cholinergic transmission at nicotinic receptors (Morishita et al. 2010), and by the binding of Otx2 to perineuronal nets around PV-expressing basket cells (Beurdeley et al. 2012). Whether these same mechanisms abolish plasticity in fully adult animals remains unclear, but our results show that any such mechanism must involve cortical interneurons. Transplantation of CGE fails to induce ocular dominance plasticity For a variety of reasons, research on critical period induction has focused on parvalbumin-containing interneurons (Cellerino et al. 1992; Hensch et al. 1998; Sugiyama et al. 2008; Yazaki-Sugiyama et al. 2009), and it seemed natural to assume that only this class of cells was responsible for the plasticity-enhancing effect of transplanted MGE cells (Southwell et al. 2010). Most recently, however, it has been shown that somatostatin-containing, dendrite-innervating interneurons, which also arise from the MGE, are equally capable of inducing ocular dominance plasticity (Tang et al. 2014). It is, therefore, remarkable that CGE explants, which give rise to diverse forms of mature interneurons, failed to induce plasticity in the present as well as in a concurrent (Davis et al. 2015) study. In both studies, the transplanted CGE-derived cells preferentially settled in deep cortical layers, although intrinsic inhibitory interneurons from the CGE are mostly found in superficial layers (Miyoshi et al. 2010). Davis and colleagues hypothesized that this ectopic integration might be the reason for their failure to induce plasticity. In the present study, however, MGE-derived interneurons likewise migrated mostly into subgranular layers, but nevertheless induced plasticity. This suggests that it is the cell type rather than cell position which decides on whether plasticity is released by transplanted neurons. The way by which MGE-derived transplanted interneurons induce plasticity still remains mysterious. While it has been shown that they increase both inhibition of intrinsic excitatory cells (Alvarez-Dolado et al. 2006; Southwell et al. 2012) and ocular dominance plasticity (Davis et al. 2015) independently of their density, a direct augmentation of inhibition by diazepam treatment does not induce plasticity in adult mice (Fagiolini and Hensch 2000). Moreover, the opposite intervention, namely reducing inhibition, can also reinstate ocular dominance plasticity in adult animals (Harauzov et al. 2010). Recent research has shown that activation of the transcription factor Npas4, the net result of which is an increase in network inhibition (Spiegel et al. 2014), is both necessary and sufficient for critical period-like ocular dominance

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plasticity in adult rats (Maya-Vetencourt et al. 2012). It seems possible that additional MGE-derived interneurons reactivate this genetic program by their specific effects onto the local network. Research of the last years has elucidated inhibitory circuits regulating plasticity (Fu et al. 2014, 2015; Kaneko and Stryker 2014). These circuits prominently involve VIPcontaining interneurons derived from the CGE, which, synapsing onto somatostatin-containing cells, mediate a disinhibition of principal cells. As adding CGE-derived cells to the adult cortex did not induce plasticity in the present study, the functional influence of the new cells onto the cortical network remains to be investigated.

Conclusion In recent years, the transplantation of MGE-derived cells has been used to successfully treat a large variety of animal models for neurological and psychiatric disorders that are supposedly caused by either defects in GABAergic cells [so-called interneuronopathies, (Marin 2012)] or shifts in the excitation–inhibition balance. For instance, a substantial amelioration of symptoms was observed in models of epilepsy (Hunt et al. 2013), Alzheimer’s disease (Tong et al. 2014), Parkinson’s disease (Martinez-Cerdeno et al. 2010), or schizophrenia (Tanaka et al. 2011) (see Southwell et al. 2014 for a recent review). Our results show that the transplantation of specific classes of interneurons is capable of rejuvenating the cortex even at an advanced age, and that, therefore, the capacity for substantial plasticity is preserved in the cortex throughout life. Acknowledgments We are grateful to Vanessa Kno¨lker for help with data analysis, Elisabeth Meier for excellent technical assistance, and to Sandra Clemens for animal care. We further wish to thank Prof. Christian Hu¨bner and Dr. Lutz Liebmann (Institute for Human Genetics, Jena) for their willingness to cooperate, and Dr. Annika Do¨ding for proof-reading the manuscript.

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