Signals and Signalling Mechanisms in the Central Nervous System Our brain is a network of about 1011 neurons, which are connected by synapses. A neuron typically receives input from about 10000 other neurons, which can be either excitatory or inhibitory. The neuron integrates these inputs and generates an ‘action potential’ (or an electrical nerve impulse), when its membrane potential surpasses a certain threshold. This impulse travels along the nerve fiber and excites or inhibits thousands of other neurons, to which the fiber is connected via synapses. My work over the last 40 years has been concerned with the two most basic signaling mechanisms in the brain: ion channels, which mediate the electrical excitability of nerve fibers and neurotransmitter release, which is the process, by which a nerve ending sends a signal to the receiving or ‘postsynaptic’ cell. In the first part of this lecture I will give an overview over the early studies (together with Bert Sakmann) on the development of the patch clamp technique, which allowed us to record currents flowing through individual ion channels and I will explain how the availability of a new sensitive recording technique led to the discovery of a multitude of ion channel types, which fulfill numerous signaling tasks in basically all types of tissues and organisms. In the second part I report on some more recent findings regarding the Ca++-dependence of neurotransmitter release and the mechanisms of short-term synaptic plasticity. The term ‘synaptic plasticity’ describes the fact that connection strengths between the neurons of our brain change constantly in a use-dependent manner. These changes occur on many time scales and underly many of the computational capabilities of our brain. Molecular mechanisms for the fast forms, so-called ‘short-term plasticity’, are still a matter of debate. The ‘Calyx of Held‘, a glutamatergic presynaptic terminal in the auditory pathway has unique properties for the study of neurotransmitter release. It is large enough that quantitative biophysical techniques, such as voltage clamp, Ca++ fluorimetry, and Ca++-ions uncaging can be applied. Using these experimental tools, we have studied the role of Ca++ and other second messengers in neurotransmitter release and short-term synaptic plasticity (see E. Neher and T. Sakaba, 2008, Neuron 59, 861-872 for review). The lecture will cover a number of biophysically interesting aspects of neurotransmitter release, such as the amplitude and time-course of the ‘nanodomain Ca++ signal’ near open channels, which triggers release, and the depletion and refilling of synaptic vesicle pools.