The central nervous system

The human brain is the most complex biological structure on earth. It performs a large variety of complex tasks, including the reception, processing, integration and storage of information. In addition, by controlling the central and peripheral nervous system it controls and adapts body functions and motor behavior.

In the beginning of the 20th century Santiago Ramón y Cajal layed the foundation for our understanding of the nervous system by describing its central information processing unit, the neuron. The human brain consists of approximately 10¹¹ neurons (Brose, 1999). These neurons are electrically excitable cells that form neuronal networks (Fig. 1). In order to achieve higher brain functions, neurons communicate with each other via two kinds of elaborations: multiple dendrites, which receive incoming informations and send them to the cell soma, and a single axon that passes electrical informations on to the next cell.

If the electrical excitation of a neuron reaches a certain threshold, an action potential is generated at the axon hillock and travels along the axon and eventually reaches a nerve terminal, the synapse. Neurons communicate via 10¹⁴ to 10¹⁵ of these synapses (Brose, 1999). At the synapse the plasma membranes of two cells come into close proximity and form a synaptic cleft. Both, the pre- and the postsynaptic membrane are specialized to transmit information from one cell to another. Neurons communicate with each other through electrical and chemical signals. Besides rare electrical synapses, the majority of neurons in the vertebrate central nervous system (CNS) communicate via chemical synapses. During neuronal communication an action potential that reaches a synapse triggers the fusion of synaptic vesicles with the presynaptic membrane. These vesicles contain neurotransmitters, that are released into the synaptic cleft and thereby transform electrical information into chemical signals. Neurotransmitters bind to receptors in the postsynapse. Depending on the neurotransmitter released and the neurotransmitter receptor it binds to, different postsynaptic reactions are triggered. Two kinds of neurotransmitter receptors exist in the nervous system, ligand-gated (ionotropic) receptors and G-protein-coupled (metabotropic) receptors. Ionotropic receptors can either be excited, by neurotransmitters like glutamate or aspartate, or inhibited by ligands like GABA or glycine. Metabotropic receptors are not directly channel-linked. Upon ligand binding a conformational change is induced, which allows the receptor to activate adapter molecules, so called G-proteins, by exchanging their bond GDP by GTP. Thereupon, the G-protein dissociates and effects intracellular signaling cascades, that ultimately

lead to ion channel opening or altered gene expression, and therefore can induce long-term changes in the activated cell (Kandel, 2013).

Cortical networks comprise two classes of neurons: excitatory (mostly glutamatergic) pyramidal neurons and inhibitory (mostly GABAergic) interneurons (Fig. 1).

Pyramidal neurons process sensory or motor informations and generate output signals, that control other parts of the nervous system and body, including muscles in the periphery. Interneurons connect locally between neurons, are typically inhibitory and modulate the activity of pyramidal neurons by finetuning their excitability. In line with their different function, pyramidal neurons and interneurons also originate from different brain regions and progenitor cells. While excitatory neurons derive from progenitors in the ventricular zone (VZ) of the pallium and migrate radially into the emerging neocortex, inhibitory neurons originate from several progenitor pools in the subpallium, from where they migrate along tangential routes to the developing neocortex, where they shift from tangential to radial migration and invade different neocortical cell layers (Marin, 2013; Marin and Müller, 2014). GABAergic interneurons can be classified into nearly 30 different subtypes based on molecular, morphological and physiological criteria (DeFelipe et al., 2013). Since they originate from distinct progenitor pools and adopt their final cortical position following specific rules, interneuronal migration is a highly complex process (Marin, 2013).

Pyramidal neurons possess two kinds of dendrites. Basal dendrites elaborate from the side of the cell body from which also the axon originates. Apical dendrites originate from the opposite side. Dendrites of pyramidal neurons possess specific synaptic microdomains, the so-called dendritic spines, at which excitatory synapses terminate (Fig. 1). Dendritic spines are equipped with a postsynaptic density (PSD), which contains neurotransmitter receptors, ion channels and enzymes that serve in synaptic neurotransmission (Kennedy, 1997; Ziff, 1997). PSD95 (postsynaptic density protein of 95 kDa) is an important component of the PSD, involved in the molecular organisation of the postsynaptic complex. Pyramidal neurons form synapses with both other excitatory (glutamatergic) pyramidal neurons and inhibitory (GABAergic) interneurons (Markram et al., 2004). Excitatory synapses on pyramidal neurons are usually formed with dendritic spines. Inhibitory interneuron dendrites usually do not form dendritic spines and excitatory synapses on interneurons are less studied, however they are also equipped with a PSD.

Fig. 1: A cortical neuronal microcircuit. A central excitatory pyramidal neuron is innervated by different classes of interneurons. Basket cells target the soma and basal dendrites of pyramidal cells, whereas chandelier cells synapse on the axon initial segment (AIS).

Martinotti and neurogliaform cells types contact pyramidal cell dendrites. Bipolar cells are specialized in targeting other interneurons (modified from Marin, 2012).

About 20-30% of neocortical neurons are inhibitory interneurons. They are morphologically diverse and their precise classification is subject to ongoing discussion (see Fig. 1 and DeFelipe et al., 2013). Inhibitory interneurons use GABA as their main neurotransmitter. Inhibitory synapses to pyramidal neurons are usually formed with dendrites, the soma and the axonal initial segment (Freund and Buzsáki, 1996; Benes and Berretta, 2001) and constitute up to 16 % of all synapses on cortical pyramidal neurons (Markram et al., 2004). Interneurons usually have smooth dendrites, without spines, and they receive excitatory and inhibitory synapses to their cell soma. Basket cells for instance usually form synapses with the perisomatic regions of pyramidal cells (Markram et al., 2004), whereas so-called „Chandelier“-cells innervate the axonal initial segment and the axon hillock (Somogyi, 1977).

„Neurogliaform“ and „double-bouquet“-cells on the other hand form synapses with dendrites of pyramidal cells (see Fig. 1 and Benes and Berretta, 2001; Markram et al., 2004). Apart from these innervation profiles, interneurons can also be classified via their molecular properties, the expression of certain marker proteins, usually calcium-binding proteins, such as parvalbumin (PV), calretinin or calbindin, but also

neuropeptides, including somatostatin, cholecystokinin (CCK), neuropeptide Y (NPY), and vasoactive intestinal peptide (VIP) (Freund and Buzsáki, 1996; DeFelipe et al., 2013). A newly imerging criterium is the origin of interneuron subpopulations, whether they originate from the medial ganglionic eminence (MGE), lateral and dorsocaudal ganglionic eminence (CGE) or the preoptic area (POA). Yet another is the classification via electrical properties. Interneurons exhibit a variety of different firing patterns, including “fast-spiking” (FS) and “Non-adapting, non-fast-spiking” (NA-NFS) cells (reviewed in DeFelipe et al., 2013). Parvalbumin-positive (PV⁺) interneurons for instance are usually fast-spiking interneurons that play an important role in the synchronization of pyramidal cell activity and the generation of -oszillations (Bartos et al., 2007).

Besides neurons, the nervous system consists of another, even more abundant cell type, the glial cells (Fig. 2). In fact glial cells outnumber neurons by 10 to 15 times (Kandel, 2013). The name glia comes from the Greek word for glue, because these cells were first thought to glue together nervous tissue. In addition to the stabilizing function, glial cells have been shown to provide several important functions, including myelination and metabolic support of axons.

Glial cells can be subdivided into two different cell classes, micro- and macroglia.

While microglia are specialized macrophages, that are mobile, serve immune functions and protect the nervous system, CNS macroglia can be further divided into oligodendrocytes and astrocytes (Fig. 2).

The main function of oligodendrocytes is the insulation of axons of the central nervous system. By enwrapping axons with multiple layers of extended plasma membrane they produce a densly packed insulating sheath, the so-called myelin sheath (Fig. 2A). Because voltage-dependent sodium channels are only present at the nodes of ranvier, action potentials jump from node to node, in saltatory impulse propagation, increasing propagation speed by ~100-fold and reducing space and energy consumption (Garbay et al., 2000; Salzer, 2003). Unlike Schwann cells in the PNS, one oligodendrocyte can myelinate multiple axonal segments (Fig. 2A). Recent results also suggest a metabolic support function for axons, that is required for functional integrity and long-term survival (Funfschilling et al., 2012; Saab et al., 2013).

Astrocytes are named after the Greek word for star (‚astron’) because of their numerous projections giving them a star shape and allow them to connect to blood vessels and other cells. They are the most abundant cell type in the human brain and support endothelial cells in building the blood-brain barrier. Thereby they provide

nutrients to the nervous tissue and also regulate the external chemical environment by removing excess ions, especially K⁺ ions. Perinodal astrocytes contact the nodes of ranvier of CNS myelin, where they are thought to buffer the extracellular ion concentrations, but also stabilize the nodes and provide nutrients (see Fig. 2A and Black and Waxman, 1988). According to the tripartite synapse theory astrocytic processes engulf neuronal synapses and not only recycle neurotransmitters, but are also thought to modulate synaptic efficacy by release of „gliotransmitters“, like glutamate or ATP (see Fig. 2B and Lalo et al., 2009; Santello and Volterra, 2009).

Fig. 2: Glial cells of the central nervous system. (A) Oligodendrocytes are the myelin forming cells of the CNS. In contrast to Schwann cells in the PNS, oligodendrocytes engulf multiple axonal segments with a myelin sheath. The myelin sheath speeds up neuronal signal propagation by saltatory impulse propagation. Perinodal astrocytes contact the nodes of ranvier, where they buffer the extracellular ion concentrations, stabilize the nodes and provide nutrients (modified from Poliak and Peles, 2003). (B) Astrocyte processes engulf neuronal synapses and form the so-called tripartite synapse. Astrocytes recycle neurotransmitters and modulate synaptic efficacy by releasing „gliotransmitters“ (modified from Allen and Barres, 2009).

Taken together the central nervous system is a highly complex and dynamic structure, which comprises multiple cell types. By cell-cell communication the nervous system can dynamically adapt and rewire, for instance during learning when

new synaptic connections are formed or some axonal pathways are strengthened, while others are retracted during development.

Apart from electrical and neurotransmitter-mediated neuronal communication, communication modules, consisting of ligands and receptors, regulate essential processes of neuronal development and maintenance. These modules are potentially involved in functions like neuronal migration, synapse formation and cortical network establishment and myelination. Defects in these signaling modules can result in impaired neuronal development and abnormalities in synaptic signaling, dysconnectivity, neuroinflammation and -degeneration. Ultimately, these processes can precipitate neurodegenerative diseases, e.g. Alzheimers disease or neuropsychiatric disorders such as schizophrenia.