Abstract
The axon initial segment (AIS) is a crucial axonal domain for neuronal function – it allows neurons to generate action potentials, maintain their polarity or modulate their own excitability, thereby adapting to sudden and more long-term changes in network state. Although the AIS has been a well-described structure in neurons with work dating back to the 1960s, its fundamental role in neuronal function has only really been appreciated in the last decade. It is therefore no surprise that the AIS now also emerges as a hub for the onset of various pathophysiological conditions. In this review, we will focus on AIS development, function, and plasticity in the context of neuronal network activity and will highlight recent results that indicate a role for the AIS in the regulation and fine-tuning of input-output relations in single neurons.
1 Introduction
Our classical understanding of CNS neurons highlights the role of the somatodendritic domain for integration of synaptic inputs and the dynamic adaption of neurons to changes in network state, particularly via plasticity at dendritic spines. The axonal domain of a neuron however, is seen as a rather static output device with little to no retained plasticity after the developmental period of neuronal networks. This classic “textbook” view is changing. A growing body of evidence suggests that electrogenic microdomains in the axon play an important role for the fine-tuning of neuronal excitability. A particular focus in this context is placed on the axon initial segment (AIS), the axonal domain responsible for action potential (AP) initiation (Fig. 1; for review see e. g. (Bender and Trussell, 2012; Kole and Stuart, 2012). Over the past decade, a number of studies have highlighted the fact that the AIS undergoes periods of structural plasticity during development, and is a hub for rapid and more long-term changes in both structure and function, directly influencing a neuron’s output and therefore its role within functional networks (for review see e. g. (Jamann et al., 2017; Wefelmeyer et al., 2016). Parameters emerging as influential for AIS plasticity are e. g. (i) its location on the axon (proximal or distal to the soma), (ii) its length, and (iii) its molecular architecture, all of which have been shown to adapt dynamically to changes in network state. Some of these examples will be discussed in this review.
A very recent “rediscovery” was that axons can emerge from a dendrite and that this has substantial effects on a neuron’s firing properties. Incidentally, it was no other than the pioneering neuroscientist Santiago Ramón y Cajal who was the first to notice that axons do not always emerge directly from the soma (Cajal, 1937). He alluded to the fact that “currents flowing into the axon do not pass through the soma except when the latter is between the dendritic and the axonal apparatus” (Cajal, 1897). Indeed, axon location is quite diverse and hence, the location of the AIS is equally heterogeneous and often cell type specific (Fig. 1A; (Ernst et al., 2018; Hamada et al., 2016; Hausser et al., 1995; Herde et al., 2013; Hoefflin et al., 2017; Martina et al., 2000; Meza et al., 2018; Peters, 1968; Thome et al., 2014; Triarhou, 2014)). These axon and AIS phenotypes can have significant impact on the excitability and firing properties of neurons (Gulledge and Bravo, 2016; reviewed in Kole and Brette, 2018). A common denominator in these many different cell populations however is the axonal scaffold and surrounding niche that characterize the AIS.
2 Molecular architecture
The AIS of most CNS neurons is located at the unmyelinated proximal axon. It constitutes a specialized axonal microdomain distinguished from the remaining axon by several structural features specific to it and to the nodal region of nodes of Ranvier, which essentially recapitulate the AIS architecture with slight modifications (Rasband, 2010). In general, the AIS comprises a special cytoskeletal scaffold with numerous binding partners linking it to the extracellular matrix and to the inside of the axon, thus creating a highly stable compartment (Fig. 1B).
Early electron microscopy studies identified several ultrastructural features that distinguish the proximal axon, then termed ‘initial segment’, from its other parts and components of the somatodendritic domain: (i) a dense granular undercoating of the axolemma, (ii) an almost complete lack of ribosomes, and (iii) fascicles of microtubules, which can vary in density and number (Palay et al., 1968; Peters, 1968; Peters et al., 1968). Recent development of super-resolution nanoscopy has dramatically improved our understanding of AIS structural features. For example, studies using dissociated hippocampal neurons in vitro have indicated that a periodic, ~190 nm spaced submembrane lattice of the AIS consists of longitudinal, head-to-head ßIV-spectrin molecules connecting to actin rings (D’Este et al., 2015; Leterrier et al., 2017b; Leterrier et al., 2015; Zhong et al., 2014).
The axon initial segment and its molecular composition. (A)Cortical layer II/III pyramidal neurons in a Thy1-GFP animal with examples of different axon and AIS morphologies: lower left hand cell with an axon carrying dendrite (AcD cell; cell in red, AIS in yellow indicated by arrows, with immunostaining against AIS marker βIV-spectrin). Upper right hand cells both have an axon emanating from the soma, arrows indicate AIS (βIV-spectrin, yellow). Cartoons on the right highlight the two prevalent forms of axon/AIS morphology in both pyramidal cells and interneurons. (B) A cortical layer II/III pyramidal neuron filled with biocytin (developed with streptavidin, red). Surrounding cells visible by NeuN immunoreaction (blue). Only the AIS of the filled neuron is highlighted (βIV-spectrin enhanced for contrast; yellow). Boxed region is depicted in scaffold cartoon below, showing the molecular composition of the axolemma and submembrane cytoskeleton, highlighting protein interactions and the anchoring of voltage-gated ion channels and other components of the AIS (see text for details). Scale bars: A = 25 µm, B = 20 µm
The major scaffolding protein of the AIS, however, is ankyrin-G (ankG; Fig. 1B). Encoded by the ANK3 gene, ankG is known to exist as three alternatively spliced isoforms with molecular weights 480 kDa, 270 kDa and 190 kDa, respectively (Jenkins et al., 2015). It is essential for assembly and maintenance of the AIS (Hedstrom et al., 2008; Jenkins and Bennett, 2001; Leterrier et al., 2017a; Sobotzik et al., 2009; Zhou et al., 1998) and comprises a modular protein with a membrane-binding domain, a spectrin-binding domain, a serine-rich tail, as well as carboxy-rich domains (Bennett and Lorenzo, 2013). AnkG mediates linkage between axonal surface and central regions by anchoring membrane-associated surface proteins, such as voltage-gated ion channels (see chapter on AIS function for details) plus the cell adhesion molecules neurofascin 186 kDa (NF-186) and NrCAM, to axonal microtubules via interactions between microtubule-associated proteins and ankG’s carboxyterminal side (Kuijpers et al., 2016; Leterrier et al., 2011). Functionally, this highly organized architecture renders axons very stable, protecting them against cytoskeletal damage. The 480 kDa ankG isoform also plays an important role in stabilizing somatodendritic GABAergic synapses by interaction with the GABAA receptor-associated protein (GABARAP; (Tseng et al., 2015)).
While ribosomes and other molecules of translational machinery are notably absent from the axon hillock and AIS, stacks of smooth endoplasmic reticulum, termed cisternal organelle (CO), have been described (Benedeczky et al., 1994; Somogyi et al., 1983b). Interestingly, the CO and its molecular components such as the actin-binding protein synaptopodin, and Ca2+-store-associated receptors (e. g. RyR, IP3R or SERCA; (Anton-Fernandez et al., 2015; Sanchez-Ponce et al., 2011)) have a structural and potentially functional correlate in the spine apparatus of dendrites, which orchestrates spine turnover and contributes to homeostatic plasticity (Deller et al., 2007; Vlachos et al., 2013; Vlachos et al., 2009). A similar contribution to structural plasticity and cellular excitability has been proposed for the CO in the AIS (Jedlicka et al., 2008; Schluter et al., 2017; Segal, 2018). Considering that AP initiation is modulated by fast Ca2+ influx (Bender and Trussell, 2009), strategic placement of the CO in many cortical neurons points towards a significant contribution of this Ca2+-store to neuronal function. The fact that it dynamically adapts to changes in network state strengthens this hypothesis (Schluter et al., 2017).
The AIS also provides a substrate for cell contacts outside of its axolemma. Axo-axonic GABAergic interneurons (also called Chandelier cells), establish exclusive synapses with the AIS of principal neurons (reviewed in (Inan and Anderson, 2014)). First described in the 1970s (Jones, 1975; Szentagothai and Arbib, 1974), these synapses are present in numerous cortical areas and species (Somogyi, 1977; Somogyi et al., 1982; Somogyi et al., 1983a). At the AIS, the synaptic contacts locate preferentially near the CO at the axolemma (Benedeczky et al., 1994; King et al., 2014; Somogyi et al., 1983b). Intriguingly, Chandelier cells have been proposed to act as circuit switches (Woodruff and Yuste, 2008), yet whether they excite or inhibit postsynaptic pyramidal neurons is still a matter of debate and likely depends on network state (Woodruff et al., 2010; Woodruff et al., 2011). During development, they can undergo significant remodeling of their axon terminals (Fish et al., 2013; Steinecke et al., 2017; Taniguchi et al., 2013), temporally coinciding with maturation of the AIS (Pan-Vazquez et al., 2018); Jamann & Engelhardt, unpublished).
Another major function of the AIS is to contribute towards establishment of both a passive cellular diffusion barrier as well as a filter for vesicular transport, thereby sorting somatodendritic from axonal cargoes and consequently contributing to the maintenance of neuronal polarity (reviewed in (Leterrier and Dargent, 2014; Nirschl et al., 2017)). Early studies using amphibians and rodents suggest that, due to the high concentration of membrane proteins clustered at the AIS, it might serve as a “barrier” that could uphold neuronal polarity (Dotti and Simons, 1990; Matsumoto and Rosenbluth, 1985). Indeed, maintenance of neuronal polarity was shown to be severely impacted when the master regulator ankG is absent from the AIS, resulting in neurons mislocalizing dendritic and axonal cargoes both in vitro (Hedstrom et al., 2008) and in vivo (Sobotzik et al., 2009). Due to the strong immobilization of transmembrane channels by cell-adhesion molecules (CAMs) and ankG, and because membrane protein diffusion is limited at the AIS (Boiko et al., 2007; Brachet et al., 2010; Nakada et al., 2003; Winckler et al., 1999), a ‘picket fence’ model was proposed (Nakada et al., 2003). This model describes the AIS diffusion barrier as composed of mostly immobile ‘pickets’ (transmembrane channels, receptors, CAMs), while the submembrane scaffold functions as a ‘fence’ (Fig. 1). One proposed model speculates that much like the postsynaptic density, ankG-anchored transmembrane proteins may not actually serve as physical filters, but rather to limit diffusion of proteins due to the density of the scaffold itself (Leterrier, 2018).
While the mechanism of intracellular trafficking at the AIS remains controversial, it is generally accepted that both the diffusion of soluble macromolecules as well as vesicular transport are dependent on AIS-associated gatekeepers (Bentley and Banker, 2016; Song et al., 2009), which may operate independent of the ankG scaffold (Farias et al., 2015; Jenkins et al., 2015). Typically, vesicles containing axonal cargoes are preferentially sorted before entering the axon with no visible reduction in velocity at the AIS (Jenkins et al., 2015; Liu et al., 2018; Petersen et al., 2014). This is not the case for somatodendritic cargoes. By contrast, they are excluded from entering the axon or in case of unintended entry, are reversed within the AIS (Burack et al., 2000; Petersen et al., 2014; Watanabe et al., 2012), thus highlighting a potential specific sorting process at the AIS (for review see (Leterrier, 2018; Nirschl et al., 2017)).
3 AIS function
As outlined above, the AIS is the site of action potential (AP) initiation and thus critically important for neuronal network function. Despite an early appreciation that the AIS is the likely site of AP initiation (Coombs et al., 1957), a thorough understanding of why this might be so did not surface until much later. Since Hodgkin and Huxley’s groundbreaking studies (Hodgkin and Huxley, 1952a, b, c; Hodgkin and Katz, 1949a, b, c), we know that APs are critically dependent on Na+ flux. In fact, the density, distribution, and different subtypes of Na+ channels are mainly responsible for rendering the AIS as the neuronal site with the lowest threshold for AP initiation. Multiple Na+ channel subunits have been reported at the AIS whereby the exact composition depends on the studied cell type (Boiko et al., 2003; Lorincz and Nusser, 2008). However, Nav1.6 appears to be the major Na+ channel subunit at the AIS of most neurons (Hu et al., 2009; Lorincz and Nusser, 2008, 2010) and is thus the main player responsible for AP initiation. Nav1.6 channels activate at lower thresholds, more rapidly, and demonstrate less inactivation than Nav1.2 channel subunits (Colbert and Pan, 2002; Hu et al., 2009; Rush et al., 2005; Schmidt-Hieber and Bischofberger, 2010; Zhou et al., 2004; Katz et al., 2018.) They often localize distally towards the AIS end (Hu et al., 2009; Lorincz and Nusser, 2008; Van Wart et al., 2007), which is advantageous for AP initiation due to increased isolation from the capacitive load of the somatodendritic domain (Baranauskas et al., 2013; Eyal et al., 2014); reviewed in Kole and Brette, 2018). By contrast, Nav1.2 channels have been reported to localize at the proximal AIS and soma in mature pyramidal neurons of the prefrontal cortex. This specific location likely makes these channels responsible for backpropagation of APs into the somatodendritic domain, rather than participation in AP generation (Fig. 2A; (Hu et al., 2009; Yin et al., 2017)).
An often-debated topic involves the relative density of functional Na+ channels at the AIS compared to the somatodendritic domain. Immunohistochemistry and EM studies consistently demonstrate that the concentration of Na+ channels is highest at the AIS (Fig. 1; (Kole et al., 2008; Lorincz and Nusser, 2008)). However, immunostaining cannot reveal whether labelled proteins are actually functional. Furthermore, cell-attached and outside-out channel recordings reported a uniform density of Na+ channels between the soma and proximal axon (Colbert and Johnston, 1996; Colbert and Pan, 2002). A potential explanation for this discrepancy came from Kole et al., who demonstrated that the strong link of Na+ channels to the underlying cytoskeleton at the AIS can reduce the estimated channel density obtained in patch-clamp experiments (Kole et al., 2008). Using voltage-clamp and Na+ imaging experiments, they suggested that Na+ channel density is up to 50 times higher in the AIS than in the somatodendritic domain (Kole et al., 2008). However, using outside-out patches, Hu et al. estimated a 19-fold enrichment of Na+ channels at the AIS (Hu et al., 2009) and Fleidervish et al. measured only a 3-fold difference, utilizing Na+-imaging (Fleidervish et al., 2010). Interestingly, all of these studies were performed in layer V pyramidal neurons, hence a fundamental difference in cell type is unlikely to explain the discrepancies.
While general consensus has yet to be reached regarding the quantity of Na+ channels along the AIS, important insight regarding AIS function has been generated by focusing on K+ channels (Fig. 2B). Repolarization of the AP is mainly achieved by Kv3, Kv4 and Ca2+-activated BK channels (for review see (Bean, 2007)). Of note, none of these channel subtypes are reported to localize specifically to the AIS, suggesting that precise localization is not crucial for their effect on AP shape. Instead, AIS-localized K+ channels, in particular Kv1 and Kv7 channels, appear to regulate neuronal activity in a more subtle manner.
In layer V pyramidal neurons, Kv1 channels are enriched at the AIS and serve to control action potential waveform (Kole et al., 2007; Lorincz and Nusser, 2008; Shu et al., 2007). These K+ channels are active at rest and inactivate with slow, subthreshold depolarization. Once inactivated, the AP width increases, leading to increased vesicle release from presynaptic terminals (Fig. 2B; (Kole et al., 2007; Shu et al., 2007)). Kv1 channels at the AIS thus play a role beyond all-or-none AP initiation, in addition to contributing to repolarization of the AP.
Kv7.2 and Kv7.3 channels localize throughout the neuron, but are enriched at the AIS by binding to ankG (Fig. 1; (Pan et al., 2006)). They activate slowly with subthreshold depolarization and are responsible for mediating the M-current (for review see (Brown and Passmore, 2009)). At the AIS, they control AP threshold and reduce neuronal excitability (Fig. 2B; Shah et al. 2008). They also stabilize the resting membrane potential, thereby contributing to maintenance of Nav channel availability by preventing their subthreshold, depolarization-induced inactivation (Battefeld et al., 2014). They can thus both increase AP conduction as well as restrict neuronal excitability, demonstrating the complex role K+ channels play in AP generation.
Ion channels at the AIS and their function in regulating action potentials. (A) The main Na+ channel subtype responsible for AP initiation is Nav1.6, which is located at the distal end of the AIS. In some cell types, Nav1.2 is expressed proximally and thus influences backpropagation of APs into the somatodendritic domain. (B) The main K+ channel subtypes located at the AIS are Kv7 and Kv1 channels. Kv7 channels slowly activate with subthreshold depolarizations and can thus restrict repetitive firing. Kv1 channels are active at resting membrane potential and inactivate with subthreshold depolarizations, leading to an increase in AP duration. This in turn may increase neurotransmitter release. Other channels localized to the AIS include Cavs as well as neuromodulatory receptors, however, their precise role and location remain elusive. The potential functional relevance of these channels is discussed in the text.
Whether and, if so, what type of Ca2+ channels localize within the AIS is still a field of active research and appears to depend on neuronal cell type. For example, T- and R-type Ca2+ channels are enriched at the AIS in dorsal cochlear nucleus interneurons as well as in pyramidal and Purkinje cells, where they can influence AP generation and timing, particularly during complex spikes (Bender and Trussell, 2009). By contrast, Layer V pyramidal neurons of the prefrontal cortex exhibit an accumulation of P/Q and N-type Ca2+ channels at the AIS. These channels appear to increase neuronal excitability as well as contribute to AP repolarization through activation of BK Ca2+-activated K+ channels (Yu et al., 2010). Finally, AP generation can also be modulated by metabotropic receptors at the AIS, for example via 5HT1A and D3 receptors (Bender et al., 2010; Cotel et al., 2013; Yang et al., 2016; Yin et al., 2017).
4 AIS plasticity
AIS plasticity can be subdivided into two categories: developmental plasticity and plasticity elicited by changes in network state in mature neurons (Fig. 3). In cell type-specific manners, the first emergence of AIS in developing neurons can be detected as early as E9.5 in mouse motoneurons (Le Bras et al., 2014) and E14.5 in mouse cortical neurons and Cajal-Retzius cells (Gutzmann et al., 2014). In higher mammalian NPY-positive interneurons (Sus scrofa), the first AIS appear around E70 and exhibit both a length increase and proximal shift until P30 (Ernst et al., 2018). Structurally, the AIS matures during periods of activity-dependent plasticity in sensory systems of mice (Fig. 3A; (Gutzmann et al., 2014; Schluter et al., 2017)) and of chicken (Kuba and Ohmori, 2009; Kuba et al., 2010), a feature so far not observed in non-sensory cortices (Gutzmann et al., 2014). Furthermore, reduction of AIS length during postnatal development has also been observed in nonhuman primate prefrontal cortex (Cruz et al., 2009; Fish et al., 2013).
The first evidence that AIS structure is dynamic and can be modulated by manipulating neuronal activity came from two hallmark papers in 2010 (Fig. 3B-C; (Grubb and Burrone, 2010; Kuba et al., 2010). Grubb and Burrone demonstrated that augmenting neuronal activity in vitro, either by using an increased K+ concentration in the extracellular medium or by optogenetic stimulation of individual pyramidal cells in hippocampal neurons leads to distal relocation of the entire AIS. This plasticity was accompanied by reduction in intrinsic excitability, suggesting that it serves a homeostatic purpose of attempting to reduce neuronal activity back to more normal levels. Kuba et al. demonstrated that reducing neuronal activity by removing sensory input can also impact the AIS. After removal of cochlea in the chick in vivo, AIS length increased in nucleus magnocellularis neurons. Immunostaining indicated that this also increased distribution of Na+ channels at the AIS, which can explain the observed increase in excitability.
Taken together, these results suggest that this second form of AIS plasticity equally serves a homeostatic purpose, namely to increase excitability after a loss of presynaptic input. In a follow-up study using the chick auditory system, Kuba et al. showed that AIS elongation was accompanied by a change in expression of K+ channels: Kv1 channel expression decreased, whereas Kv7 channel density increased (Kuba et al., 2015). Since Kv7 channels have much slower activation kinetics compared to Kv1, this further serves to increase neuronal activity by reducing the shunting conductance during AP initiation. This finding is intriguing because it links structural and intrinsic plasticity and suggests that this might also occur in other models of AIS plasticity, especially given the tight link between structure and function in this domain. Grubb and Burrone observed no changes in AIS Na+ channel distribution in their original study, yet whether K+ channel expression might have changed remains unclear. However, in a follow-up study using organotypic hippocampal slices, Wefelmeyer et al. demonstrated that the shift in AIS location is not reciprocated by the axo-axonic synapses formed by Chandelier cells onto the AIS of principal neurons (Wefelmeyer et al., 2015). This creates a mismatch between the position of the AIS and its synapses, and likely contributes to the homeostatic decrease in excitability by increasing the amount of GABAergic synapses located between the soma and the site of AP initiation.
Both a shift in AIS position (Chand et al., 2015; Evans et al., 2015; Hamada and Kole, 2015; Hatch et al., 2017; Lezmy et al., 2017; Wefelmeyer et al., 2015), as well as a change in AIS length (Baalman et al., 2013; Engelhardt et al., 2018; Kaphzan et al., 2011; Kuba et al., 2015; Vascak et al., 2017) have since been observed repeatedly in vitro and in vivo including in disease models (Fig. 3D). It remains an open debate whether AIS-specific alterations are causal to, or simply correlate with disease phenotypes. As can be expected, mutations in the various isoforms of voltage-gated ion channels clustered at the AIS have been linked to numerous forms of epilepsy (reviewed in (Child and Benarroch, 2014; Wimmer et al., 2010). Similarly, conditions that result in changes of network state such as Angelman syndrome (Fig. 3D; (Kaphzan et al., 2011)), Alzheimer’s disease (Hatch et al., 2017), or demyelination pathologies (Hamada and Kole, 2015) can lead to structural AIS modifications with functional implications for neuronal firing properties. Likewise, misguided axonal vesicle sorting observed in neurodegenerative diseases has been associated with the AIS (Zempel et al., 2017). However, at this point, the most plausible role of AIS in human disease is linked to mutations in ANK3. Several genome-wide association studies have shown ANK3 to be associated with neurodevelopmental disorders including bipolar disorder, schizophrenia, and autism spectrum disorders (Iqbal et al., 2013; Schizophrenia Psychiatric Genome-Wide Association Study, 2011; Zhu et al., 2017).
AIS plasticity. (A) During development of sensory systems, AIS of cortical pyramidal neurons gradually increase in length until the onset of synaptic drive (e. g. eye opening, active whisking), which then results in significant length reduction. This process is activity-dependent. (B) Sensory deprivation in vivo reduces synaptic drive and leads to AIS elongation and increased cellular excitability. (C) Chronic stimulation in vitro with increased synaptic drive results in both AIS shortening and a distal shift. During the latter, axo-axonic synapses remain in place, therefore further reducing cellular excitability. (D) AIS remodeling under various pathophysiological conditions can result in both length and position changes. See text for details. AIS in this cartoon are not scaled to actual cell size but rather exaggerated for visualization purposes.
While most of the above-mentioned studies have shown AIS plasticity after long-term manipulation, shorter-term plasticity has also been observed. Two recent studies demonstrating AIS plasticity after brief manipulations intriguingly both involve the M-current mediated by Kv7 channels, either only seconds after acetylcholine release or after an hour of cholinergic stimulation (Lezmy et al., 2017; Martinello et al., 2015). Evans et al. observed an AIS shortening in vitro after only three hours of treatment in hippocampal neurons (Evans et al., 2015). This observation might pertain to a precursor of the distal AIS shift seen after using the same stimulation protocol for two days (Evans et al., 2013; Grubb and Burrone, 2010), since both types of plasticity are mediated by L-type Ca2+ channels and calcineurin.
5 Outlook
Clearly, various forms of AIS plasticity exist and depend on cell type, experimental conditions and time-scales observed. It is important to note, however, that the vast majority of these plasticity mechanisms appear to be homeostatic in nature. We therefore propose that the AIS is a key hub for neuronal network homeostasis. At present, numerous questions remain unanswered. For example, which precise biophysical properties underlie AP initiation? Which mechanism(s) drive(s) AIS plasticity? How is the rigid AIS scaffold organized when the domain undergoes length changes or relocates along the axon? How does AIS plasticity contribute to network function? How do mutations in ANK3 contribute to the etiology of neurodevelopmental disorders? Fortunately, the wealth of new research that has emerged in recent years has sparked a great deal of interest in the field and we can look forward to further boosts in understanding the axon initial segment in the near future.
About the authors
Maren Engelhardt studied Biology at Ruhr-University Bochum and received her PhD in Neuroscience from the Dept of Neurobiology at Regensburg University in 2005. After a postdoc at the University of California in Los Angeles (UCLA) from 2005–2010, she joined the Institute of Neuroanatomy at the Medical Faculty Mannheim of Heidelberg University as a group leader in late 2010. Since 2016, she is also the acting head of Microscopic Anatomy and Histopathology in Mannheim.
Nora Jamann studied Medicine at the Medical Faculty Mannheim of Heidelberg University and joined the Institute of Neuroanatomy in 2014 for her experimental medical thesis. She has spent time abroad for lab rotations and as part of her medical education at the Universidad Andrés Bello in Santiago, Chile and the Centre Hospitalier Universitaire de Butare in Rwanda, Africa.
Winnie Wefelmeyer studied Bioinformatics at the Free University Berlin, then joined the Wellcome Trust program in Neuroscience at the University of Oxford, where she obtained her DPhil at the Department of Pharmacology in 2011. Since then, she has been a Postdoc at the Centre for Developmental Neurobiology at King’s College London in the UK. She recently received a Daniel Turnberg Travel Fellowship to spend time in Israel and foster collaborations.
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