Jasper's Basic Mechanisms of the Epilepsies Jasper's Basic Mechanisms of the Epilepsies Perturbations of Dendritic Excitability in Epilepsy Cha-Min Tang1 Scott M. Thompson2 1 Departments of Neurology and Physiology, University of Maryland School of Medicine; Baltimore VA, Medical Center 2 Department of Physiology, University of Maryland School of Medicine Abstract The dendritic arbor is the site of complex interactions between synaptic excitation and intrinsic excitability. It has become apparent recently, that the dendritic arbor cannot be viewed as a passive antenna that simply receives and relays synaptic input to the cell body. Instead, dendrites express an abundance of voltage-gated channels that are capable of initiating regenerative spikes and actively regulate the local dendritic resting membrane potential. Active properties can be expressed as back- propagating action potentials along the main apical trunk and as localized spikes confined to individual terminal dendritic segments. The notion of the dendritic arbor as a highly active structure has profound implications for the generation of epilepsy. This chapter will focus on recent data on perturbations to dendritic intrinsic excitability associated with epileptic conditions. An attempt will be made to understand how hyperexcitability may be the result of maladaptive homeostatic mechanism. Topics to be addressed relevant to the functional reorganization of dendrites include activity-dependent down regulation of IA (Kv4.2), epilepsy induced down regulation of Ih (HCN1 and HCN2), and deafferentation induced down regulation of SK-type potassium channels. Other topics to be addressed include the concept of electrical compartmentalization within the dendritic arbor and the recruitment of NMDA receptors as part of intrinsic excitability. A clearer understanding of dendritic mechanisms of neuronal hyperexcitability may offer novel insights for therapeutic interventions. The dendrite is where the thousands of excitatory and inhibitory synaptic inputs are received by the neuron. But rather than just being a simple antenna, the dendrite is also where these inputs actively interact with intrinsic conductances. The interactions are complex and still incompletely understood. The synaptic inputs are distributed in time and space, and each of the many intrinsic dendritic conductances are also distributed in their own unique spatial pattern. The interactions lead to signal transformations whose significance may be best appreciated in terms of elementary steps in signal processing and computation. Under pathological conditions, changes to these interactions may result in aberrant excitability and contribute to neurological disease. Rather than compiling a list of dendritic conductances and their linkages with epilepsy, which is done in other chapters of this book, the focus of this chapter is to integrate these results with an emphasis on how perturbations of the elementary steps in dendritic integration affect the way neurons process their inputs and promote aberrant neuronal excitability. A brief history of the active dendrite Our view of the role of dendrites in epilepsy has evolved with increased understanding of the roles dendrites serve in normal physiology. For most of the last century, the dendritic arbor was viewed as a structure that gathered and faithfully funneled inputs to the soma and axon hillock, where non-linear processing - in the form of action potential initiation - was thought to reside. This view of the dendrite as a passive antenna would not suggest that the dendrite Page 2 plays a pivotal role in neuronal hyperexcitability. The possibility that apical dendrites of pyramidal neurons are active was first demonstrated by Spencer and Kandel when they described events they called “fast prepotentials” (1). Similar “dendritic spikes” were reported Jasper's Basic Mechanisms of the Epilepsies Jasper's Basic Mechanisms of the Epilepsies from neocortical neurons by Purpura (2). The concept of the active dendrite was further advanced with demonstration of calcium electrogenesis in dendrites by Llinas, Schwartzkroin, Wong, Prince, and Sakmann (3–6). Magee and Johnston further extended the concept of the active dendrite by demonstrating high levels of expression of sodium channels throughout the apical trunk in hippocampal pyramidal neurons (7). Simultaneously, Stuart and Sakmann and others showed that action potential can propagate bidirectionally in the dendritic arbor (8). This bidirectional signaling provided the means for coincidence detection, which was postulated to serve an important role in triggering acute and long term changes in excitability such as spike timing dependent plasticity (STDP) (9). Several others in Johnston’s and Sakmann’s groups also investigated the properties of calcium electrogenesis at the apical tuft region of layer 5 pyramidal neurons, showing that these calcium channels help amplify synaptic inputs from the more distal branches (10–12) and that back propagating action potentials (bAPs) can trigger calcium spikes localized to the apical tuft (13). Next, Schiller and colleagues demonstrated the ability of NMDA receptors to generate local spikes on tertiary basal dendrites of cortical pyramidal neurons (14). The capacity of NMDA receptors for regenerative depolarization under appropriate conditions provided an additional mechanism of excitability that is unique to dendrites and not observed in other excitable membranes such as axons and muscle. Thus, over a span of 20 to 30 years, the view of the dendrite as a passive antenna evolved to that of a highly excitable structure that rivaled the soma. This change in perspective also led to a greater interest and understanding of the role of dendritic excitability in epilepsy. Electrical compartmentalization of dendrites: the intersection of form and function The organization of this chapter is based on the premise that dendrites serve signal processing and computational needs that are fundamental to the function of nervous system. Because non- trivial computation generally requires some form of non-linear operation, it is informative to examine the source of non-linearity in dendritic integration. One obvious source of non- linearity is active conductances. A less obvious but important determinant of nonlinearity is electrical compartmentalization. Electrical compartmentalization is like the parenthesis in mathematics. It separates those variables that are included in an operation from those that are excluded. The ability to segregate variables and “bind” them for non-linear operations is as fundamental to orderly signal processing as it is in mathematics. At the level of the dendrite, binding of synaptic inputs can be implemented by electrical compartmentalization within different regions of the dendritic arbor and individual dendritic segments (16–18). Electrical compartmentalization can be functionally defined as a condition in which local interactions within a confined space occur quasi-independently from the influence of the rest of the cell. At rest, all dendritic regions are close to isopotential. During activity, a region of the dendritic arbor (i.e., a “compartment”) may be at a membrane potential that is significantly different from the potential of other nearby dendrites and the cell body. For example, nearly synchronous activity in a set of synaptic inputs that arrive on a single dendritic segment can trigger a variety of active electrical responses, such as plateau potentials (16). These responses functionally bind together the original inputs and are amplified and transmitted to the soma reliably. In contrast, inputs arriving on different dendritic branches, or arrive with insufficient temporal synchrony to allow such binding, will fail to trigger active dendritic responses; consequently, they will not be amplified and will exert lesser influence on the output of the neuron. Perturbations of Dendritic Excitability in Epilepsy Page 3 Electrical compartmentalization is determined by three factors: the passive electronic properties of the dendritic arbor; the expression of active conductances on these structures; and the temporal-spatial pattern of excitation. Factors favoring compartmentalization within the Jasper's Basic Mechanisms of the Epilepsies Jasper's Basic Mechanisms of the Epilepsies dendritic tree are high output impedance of the dendritic segment and high expression of regenerative voltage-dependent conductances. Electrical compartmentalization can be dynamic, and changes in the extent of ongoing synaptic activity(both excitatory and inhibitory) can change the impedance of the dendrite. Because the voltage-dependent blockade of NMDA receptors by Mg2+ can effectively add a non-linear excitability to the dendritic, the tempo- spatial pattern of synaptic excitation within a dendritic domain is a strong determinant of the extent of the compartment. Two functional dendritic compartments will be discussed in detail in the context of epileptogenesis. One is the compartment comprising of the individual terminal dendritic branches, which receive >80% of synaptic inputs to pyramidal neurons (19). The other is the region on the distal apical trunk, near the base of the apical dendritic tuft, which has a high propensity for generating calcium spikes (6,20). Experimental observation has shown that distal and proximal dendritic compartments express distinct intrinsic conductances. In fact, dendritic information processing can be modeled as a two layer system of distal and apical domains,