1 Mechanisms of Brain Plasticity From Normal Brain Function to Pathology

8/6/2019 1 Mechanisms of Brain Plasticity From Normal Brain Function to Pathology

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MECHANISMS OF BRAIN PLASTICITY:FROM NORMAL BRAINFUNCTION TO PATHOLOGY

Phi lip A. SchwartzkroinDepartme nt of Neurolo gical Surgery, University of Washington, Sea ttle, Washington

I. IntroductionII. Relationships between Neuropathology and Plasticity

III. SummaryReferences

1. Introduction

In modern neuroscience, there is a growing recognition of an inti-mate, but also very complex, relationship between those neural processesthat underlie normal brain function and those mechanisms that give riseto neuropathologies. In particular, mechanisms that we now call plas-tic appear to play a major role in many neurological disorders in whichneuronal reorganization is a major factor. Nowhere is this relationshipmore obvious and important than in the development of a chronicseizure state, that is, in epileptogenesis. This connection is one on whichFrank Morrell focused throughout his pioneering career in basic andclin ical neuroscience (Morrell, 1959-1960, 1989; Morrell et al., 1993).The goal of this chapter is to highlight a number of neuroplastic processesthat we believe to be critical to normal brain function, and explore theirpotential involvement in epileptic processes. In the course of this dis-cussion, I make the case that there is a strong connection between neu-ropathologies such as epilepsy and normal brain plast icity, such that thedistinction between underlying mechanisms is almost impossible to dis-cern.To start, it is important to have at least a general working definitionof neuroplasticity. In my discussion, I mean by plastic ity the ability of thecentral nervous system (CNS) to alter its function, usually in response toa stimulus (internal or external) that requires a modification of the or-ganisms behavior.On the one hand, there may well be neuropathological conditions inwhich such plastic ity may not play a significant role. For example, inINTERNATIONAL REVIEW OF 1NEUROBIOLOGY, VOL. 45 Copyright Q 2001 by Academic Press.Al l rights of kproduction in a& form reserved.0074-7742101 $35.00


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2 PHILIP A. SCHWARTZKROINneurodegenerative disorders such as Alzheimers disease and Parkinsonsdisease, it does not appear that plast icity either leads to or results fromthe loss of CNS neurons that characterizes these conditions. That is notto say that plastic processes are not involved or recruited, only that plas-ticity is not a primary basis (or contributor) to these neuropathologies.On the other hand, epileptogenesis may be a direct product of plasticprocesses such as synaptic potentiation and/or sprouting (see below).And seizures may lead to significant neuronal loss and glial reactivity,providing an essential stimulus for changes in neuronal structure andfunction, for example, in the reorganization that appears to be de-signed to compensate for the injury.Plas ticity and concomitant changes in brain excitability are not newconcepts in neuroscience. We have long been aware of such phenomenaas:

a. Denervation receptor sensitization (Kuffler, 1943): Denervation su-persensitivity was described quite early as dramatic changes in the acetyl-choline (ACh) receptors at the neuromuscular junction of denervatedmuscle. Hypersensitivity of the muscle to applied ACh is now known tobe a function of changes in receptor localization, density, and molecularsubunit composition of the receptors (Gu and Hall, 1988). Interestingly,there was considerable controversy about whether these receptor changeswere due to loss of activ ity in the muscle itself, absence of released ACh,or loss of some trophic factor released by the nerve terminal (along withneurotransmitter) onto the postsynpatic target (L@mo and Rosenthal,1972). Such questions remain very much a part of the research programfocused on mechanisms of epileptogenesis (Swann, 1995).b. Changes in neuronal electrical properties following CNS damage (Kunoand Llinas, 1970). Every electrophysiologist knows that injured neuronsdischarge differently from healthy cells. Although it remains unclearwhat aspects of injury result in which electrophysiological changes, alarge variety of alterations have been reported, including development ofdendritic spikeinitiation zones (Purpura et al., 1966), axonal backfiring(Lisney and Devor, 1987; Gutnick and Prince, 1972), and changes in in-put resistance (Gao et al., 1999). Since it is now clear that seizures can(and do) sometimes lead to cell injury, it is relevant to assess whether in-jury-related changes can alter general excitability. This issue becomeseven more complex when one takes into account the likelihood thatinjury-induced changes in glia (astrocytes and/or microglia) may be trans-mitted to neuronal elements quite directly (Duff, and MacVicar, 1999).c. Sprouting and development of new circuits (Cotman and Nadler, 1978).The sprouting phenomenon has been studied within the context of a


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NEUROPLASTICITY AND EPILEPTOGENESIS 3number of neuropathological and learning conditions (Tsukahara, 1985).Notably, an early focus of this research was on spinal cord injury, wheresprouting was proposed as a basis of spasticity (McCouch et al., 1958;Goldberger and Murray, 1988). The development of new and/or aber-rant axonal collaterals and functional synapses has long been associatedwith development of hyperexcitable responsiveness, although few stud-ies have adequately considered the possibility that these new connectionsmight underlie enhanced inhibition meant to dampen the effects of theneuropathological condition. Sprouting-like phenomena have also beenconsidered within the context of normal learning, especially in studiesassociated with animal exposure to enriched environments and/or highlevels of activ ity (Rosenzweig and Bennett, 1996).

More recent studies of plastic ity have focused on alterations at the ge-netic and molecular levels (Wheal et al., 1998). In particular, alterationsin glutamate and y-aminobutyric acid A (GABA-A) receptor subunitcomposition have been examined in a variety of behavioral and electro-physiological protocols. Most prominent among this group of studies arethose focused on changes in synaptic efficacy as a function of activ ity atthat synapse, that is, long-term potentiation (LTP) (Thomas et al., 1996).

Within the context of epileptic pathologies, it has been somewhat con-troversial as to whether such plast ic processes are initiated by some in-jury/cell death insult or whether they are activity-dependent processesthat can occur in the absence of any overt cell damage. Modern neuro-biology tells us that cell death (and even neurogenesis) is an integral as-pect of brain development, maintenance, and function. If that is the case,then the normal CNS must also be constantly involved in circuitry reor-ganization and establishment of new synaptic contacts. However, for mostresearchers interested in CNS plasticity, it is the activity-dependent set ofprocesses that have captured the lions share of attention. It is here thatthe plast icity associated with establishment of normal brain circuits,with normal learning processes, is thought to occur. Plastic ity surelycan occur in the absence of pathology. The question is whether such nor-mal plastic mechanisms can, in some cases, give rise to pathologies.Clearly, Frank Morrell (and many others) believed that he had found adramatic example of such injury-independent plastic ity in the phenome-non of kindling and/or in the development of secondary epileptic foci.How is it that plasticity and pathology should be so close ly inter-twined, that pathology can initiate plasticity, and vice versa? I suggestthat this interrelationship is an inevitable consequence of the fact thatthey share so many underlying mechanisms. Normal brain plastic ity andneuropathology simply represent different points on the continuum of


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4 PHILIP A. SCHWARTZKROIN

cellular mechanisms that have evolved-and have come to a peak ofcomplexity-in the mammalian CNS. As a corollary to this proposal, Iwould also maintain that normal plast icity in the mammalian CNS re-sults from a delicate balancing act, requiring rather precise interplay be-tween excitatory and inhibitory mechanisms. Pathologies, for exam-ple, seizures, occur when these balances fail.Why design such an apparently unstable system? What is the ratio-nale for placing the organism at such risk? The answers to these ques-tions revolve around the means by which a system (the central nervoussystem) can be designed to optimize plasticity , indeed, in which plas-ticity is its primary mission. The Grand Designer, in his or her greatwisdom, developed a system that could respond readily to different en-vironmental conditions, that could learn complex tasks in response todifficult challenges, that could generalize behaviors to new environ-ments-much as is the case for the immune system (with which the CNSappears to have much in common). This optimization of plastic neuronalprocesses and of circu it reorganizational capabilities, however, comes ata price, for processes that are designed to support change are intrinsi-cally unstable. Thus, as the potential for plastic ity increases, so also doesthe danger of system failure, or at least system dysregulation. My viewis that our CNS reflects a compromise design, in which some subcom-ponents of the system are quite stable but relatively nonplastic (e.g.,those systems responsible for basic vegetative functions), while othercomponents exhibit easily-triggered plastic capabilities. The parts of thesystem to which we have been drawn in trying to understand higherbrain function-those brain regions that seem so much involved in nor-mal plasticity-are precisely those that are at greatest risk.Such a viewpoint is, of course, inherently philosophical (i.e., I cannotprove any of these proposals) and suffers from a strong teleological mo-tivation. But there are a number of interesting relationships betweenneuropathology (i.e., epilepsy) and plast icity that are, at the very least,consistent with this thesis.

II. Relationships between Neuropathology and Plasticity

1. Regions specialized for learning/memory (i.e., plast icity) are most prone toseizures. In thinking about brain regions that are particularly seizure-prone, we tend to focus on neocortical regions and particular ly hip-pocampus, precisely those parts of the brain that we have also implicatedin complex cognitive functions, e.g., learning and memory. We gener-


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NEUROPIBTICITY AND EPILEPTOGENESIS 5

ally think of these cortical regions as having evolved precisely to take onthe complex tasks that now characterize higher organisms (particularlyin mammals). What features of cortica l organization might subserve bothplast icity and epileptogenicity? Certainly, there are a number of suchcharacteristics:

a. Laminar organization: Laminar organization and the regular rep-etition of cortica l structural units (e.g., columns, lamellae) have beenstudied as structural units of function (Mountcastle, 1997). This type oforganization gives rise to large extracellular currents and synchroniza-tion of cell populations-the bases of electroencephalographic activ itiesand rhythmic activit ies such as sleep spindles and theta rhythm(Creutzfeldt et al., 1966). The currents generated by these highly orga-nized units can provide a potent mechanism for synchronization andspread of excitation (Dudek et al., 1986).b. Recurrent circu its (excitatory and inhibitory): Recurrent axonalconnectivity provides feedback that many investigators have found to becrit ical in their models of information processing (Buzsaki et al., 1990).Excitatory feedback loops have been associated with hypersynchrony ofbrain regions thought to act as pacemakers for epileptiform activ ity(e.g., the CA3 region of hippocampus) (Traub and Miles, 1991), andsubserve epileptogenesis of other brain regions following injury and/orinsult (Esclapez et al., 1999). Inhibitory feedback loops have long beenstudied as a basis for rhythmic electroencephalographic activ ities (Lopesda Silva et al., 1976) and are now associated with network bindingproperties so key to current theories of learning and memory (Traubet al., 1996). Such circuits, for example, in corticothalamic loops, are alsothought to be the generators of spike-wave discharge characteristic ofabsence-like seizure activ ity (McCormick and Bal, 1997).c. N-Methyl-n-aspartate (NMDA) receptor function. High levels ofNMDA receptors reflect a neuronal system in which synaptic plastic ity(e.g., long-term potentiation) is optimized. Glutamatergic excitation inhippocampus and neocortex is mediated by postsynaptic potentials witha significant NMDA receptor-mediated component, and both structuresdemonstrate dramatic synaptic potentiation phenomena triggeredthrough NMDA receptor mechanisms (Nicoll and Malenka, 1999).NMDA receptor antagonists (e.g., MK-801) are also known to have po-tent antiepileptic properties (Williamson and Lothman, 1989). Their useas antiepileptic drugs (AEDs), however, is limited precisely because oftheir significant side effects on normal cognitive function.This argument relating seizure-sensitive brain regions to those areasinvolved in, for example, learning behaviors, would be more convincing


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6 PHILIP A. SCHWARTZKROINif the relationship were simple (i.e., if there were a clear correlation be-tween regions devoted to plastic processes and those most often involvedin seizure generation). The situation is, however, admittedly murky, forhow does one-objectively-compare degree of plast icity across brain re-gions? Is the hippocampus really more plastic than, for example, thethalamus? How can we relate plasticity to seizure propensity giventhat we really do not know (at least in most cases) what brain regionsdo (or do not) generate seizure act ivities? And then there is the discon-certing problem of the cerebellum, a structure that displays robustbehavior-related plastic ity (see Thompson et al., this volume; Thompsonand Kim, 1996), but is rarely implicated in seizure generation (Proctorand Gale, 1997) (perhaps because cerebellar cortex is primarily in-hibitory in its output). Despite these objections, one is left with an intu-itive sense that regional differences in epileptogenicity do reflect re-gional differences in the strength of underlying plastic processes thatsubserve higher cognitive functions.2. The immature CNS is thought to exhibit signi$cantly greater plastic po-tential than the adult brain and is also much more seizure-prone. We generallyrecognize that those features that we cal l plast ic in the adult are farmore robust in the developing brain. Investigators are developing an el-egant and complex story about the interplay of genes crit ical to normaldevelopment, and about the factors that endow the immature CNS withsuch great potential for repair and responsiveness to new environments(Swann, 1995; Schwartzkroin, 1995; see also Lowenstein et al., Kriegsteinet al., Sperber and Moshe, Holmes et al., this volume). It is probably notjust coincidence that the early crit ical periods of life correspond to atime of maximal synapse elaboration (Huttenlocher and Dabholkar,1997), complex pathway formation (Goodman and Shatz, 1993), and thetime of optimal seizure sensitivity (MoshC et al., 1995; see also Sperberand Moshe, Swann et al., this volume). One can point to a host of possi-ble developmental processes that are related both to the rapid growth(and dramatic plastic ity) of this period and to seizure propensity: rela-tively low levels of inhibition (Schwartzkroin, 1982; Swann et al., 1989);peak NMDA receptor concentration (McDonald and Johnston, 1990)and immature a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid(AMPA) receptors that admit calcium (Pellegrini-Giampietro et al., 1992);suboptimal regulation of extracellular ion levels (and particular ly potas-sium and chloride), perhaps due to immature activit ies of relevant pumpsand/or slow development of glia (Haglund and Schwartzkroin, 1990);robust action of neurotrophic factors (e.g., brain-derived neurotrophicfactor (BDNF) (Bonhoeffer, 1996); and so on.It is clear that many of these features provide the immature CNS


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NEUROPLASTICITY AND EPILEFTOGENESIS 7with the potential to build new circuits and to store tremendous amountsof new information in the form of gene expression and molecular syn-thesis. In addition, many investigators have begun to think of seizure-related brain features as recapitulating some of these aspects of imma-ture plastic ity, including a significant degree of neurogenesis (Parentet al., 1997), changes in receptor subunit composition (Brooks-Kayalet al., 1998), and relative nonspecificity of synaptic connections (Swannet al., 1999).3. The cellular elements that are essential building blocks of normal plastic-ity, for example, channels, receptors, second messenger signaling systems,are thefocus of our most intense investigation of epileptogenic mechanisms and the tar-gets for newly developed antiepileptic medication. We know, for example, thatreducing GABAergic inhibition facilitates LTP-like plastic mechanisms(Wigstrom and Gustafsson, 1986). Not surprisingly, augmenting GABA-mediated inhibition is the relevant function of a significant set ofantiepileptic drugs (AEDs) (including newer drugs such as vigabatrin)and of novel AED design (e.g., progesterone-related hormonal factorsthat also target the GABA receptor) (Macdonald and Kelly, 1995; Kokateet al., 1994). We also know that decreasing glutamatergic excitation, par-ticularly at NMDA receptors, blocks synaptic plast icity (Rogawski andDonevan, 1999). Both non-NMDA and NMDA antagonists have beenfound to be antiepileptic and/or antiepileptogenic (Stasheff et al., 1989;Loscher, 1998; Rogawski and Donevan, 1999). These classes of anticon-vulsants often have significant side effects, for these are drugs that workon targets cri tical not only for seizure activity, but also for normal brainfunction. This overlap of function is precisely what makes it so diffi-cult to pursue rational AED design.4. Both seizure activ ity and plastic ity are precisely controlled by inhibitoryprocesses. Volumes have been written on the crit ical role of inhibition-and its modulation-in seizure generation. Depending on the type ofseizure under study, investigators have found that synaptic inhibition isreduced (Bekenstein et al., 1993) or enhanced (Otis et al., 1994) in asso-ciation with epileptogenesis. A variety of AEDs work, at least in part,through their ability to potentiate inhibitory effects in the CNS(Macdonald and Kelly , 1995). Investigators are learning that relativelysubtle modulation of inhibitory function, through loss (or inhibition) ofinhibitory interneurons (Houser and Esclapez, 1996), alterations in thechloride gradient associated with GABAergic inhibitory postsynaptic po-tentials (IPSPs) (Prince et al., 1992), or change in the subunit composi-tion of GABA receptors (Brooks-Kayal et al., 1998), can facilitate theemergence of epileptiform activities. Not only the magnitude of inhibi-tion, but also its type (e.g., GABA-A vs GABA-B) and its localization


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8 PHILIP A. SCHWARTZKROIN(presynaptic vs postsynaptic, somatic vs dendritic) have profound influ-ences on the epileptogenicity of the CNS.

Many forms of plast icity are also greatly affected by inhibitoryprocesses. Investigators routinely block GABAergic inhibition in theirstudies of LTP, since potent synaptic inhibition masks activity-dependentLTP phenomena (Steward et al., 1990). The robust plast icity associatedwith the developing CNS occurs in the absence of mature inhibitoryprocesses; indeed, GABA-mediated synaptic events tend to be excitatoryduring much of early brain development, in many brain regions(Cherubini et al., 1991; see also Kreigstein, this volume).5. Modulation of neuronal structure and function is associated with epilep-tic as well as normal brain. A large number of neuromodulatory agents-neurotransmitters such as norepinephrine, neuropeptides such as neu-ropeptide Y (NPY) and somatostatin, neurotrophins such as BDNF,hormones such as estrogen, and extracellular messengers such as nitricoxide-are crit ical elements in our current thinking about normal brainfunction. These modulators influence the selectivity of neuronal con-nections (Kasamatsu, 1989), the birth and death of neurons (Sloviteret al., 1989), and the potential for structural reorganization (McEwen,1999). Many of these factors have also been implicated in the generationof synaptic plastic ities such as LTP and long-term depression (Schumanand Madison, 1994; Schuman, 1999). Although less well publicized, per-haps because their effects are so complex, these agents also have nowbeen shown to potently modulate seizure propensity and/or seizure con-trol. For example, it has long been recognized that lesioning the fore-brain noradrenergic pathway lowers seizure threshold (McIntyre andEdson, 1981); recent studies have confirmed the fact that loss of nor-epinephrine yields animals that are highly seizure-prone (Szot et al.,1999). Factors that upregulate during functional plasticity, for exam-ple, BDNF release during LTP (Patterson et al., 1992), are also greatlyincreased during seizure activ ity (Gall and Lauterborn, 1992). Indeed,recent studies have shown that exposure of key brain regions to highlevels of BDNF provokes seizure-like activ ity (Scharfman, 1997). Inmany cases, it remains unclear how these neuromodulators exert theireffects (e.g., investigators have noted that the immediate early gene,c-fos, is greatly increased following seizure activity, but the target(s) ofthis transcription factor remains largely unknown; Simonato et al., 1991).However, it is becoming clear that even normal fluctuations in circulat-ing factors can influence the excitability state of sensitive CNS elements.For example, circulating estrogen levels affect both normal synaptictransmission and seizure propensity (Woolley and McEwen, 1993;Woolley et al., 1997).


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NEUROPLASTICITY AND EPILEPTOGENESIS 9We can see this relationship between epilepsy and the molecular bi-

ology of plast icity emerge from current studies of LTP (induction andmaintenance) using knockout mice. Changes in the genetic regulationand molecular components of LTP pathways (see Teyler et al., this vol-ume) also seem to regulate seizure threshold and even spontaneousseizure discharge properties (e.g., in the Ca calmodulin-dependent ki-nase II knockout mouse; Butler et al., 1995). And it is now quite appar-ent that glia, which we have always suspected as playing a role in epilep-tiform activit ies (Pollen and Trachtenberg, 1970; Heinemann et al.,1999), are crit ical ly involved in the regulation of normal plasticity,through their key regulation of extracellular space, ion balance, pH, andso on (Somjen, 1975; Ransom and Sontheimer, 1992). Direct modula-tion of neuronal excitability by glia has been reported by many labora-tories (Vernadakis, 1996; Araque et al., 1998), suggesting that glial ac-tivity plays a significant role in normal brain plasticity. Glial changeshave even been reported as a feature of synaptic potentiation (Wenzelet al., 1991). It is certainly clear that manipulation of glial function, forexample, with specific channel blockers, results in altered neuronal ex-citability and facilitates epileptiform activ ities (DAmbrosio et al., 1999).6. Changes in intracellular calcium are key not only to initiating normalplastic changes, but also to initiating epileptogenic processes. One of the crit i-cal elements in almost all theories about plasticity, whether structural orfunctional, at synapses or in terms of gene expression, is intracellular cal-cium regulation. Influx of calcium and/or increases in intracellular cal-cium levels appear to be crit ical for synaptic potentiation/depression(Malenka et al., 1988; Hansel et al., 1996), for process extension andgrowth (Goldberg and Grabham, 1999), as a key signal involved in geneexpression (Shieh and Ghosh, 1999), and as an initiator of programmedcell death (Lipton and Nicotera, 1998). Calcium currents and changes inintracellular calcium concentration also appear to be critical features ofepileptiform activit ies and related neuronal pathologies (Freund et al.,1992; Speckmann et al., 1993). Calcium influx depolarizes neuronal ele-ments with a relatively slow time course, facilitating repetitive dischargeas well as initiating processes that are calcium-dependent, including syn-chronization (Manning and Sontheimer, 1997; Huguenard, 1999). Andcalcium channel blockers have been demonstrated to have antiepilepticproperties (Speckmann et al., 1993).We know that some calcium is necessary for normal function (e.g., inneurotransmitter release) (Meir et al., 1999) and that too much calciumis dangerous (can trigger cell death processes) (Choi, 1992). Here we cansee the delicate balancing act at work quite clearly. How much calciumis enough? What routes of calcium entry (or intracellular calcium re-


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10 PHILIP A. SCHWARTZKROINlease) are normal and what processes pathological? How does the lo-calization of calcium alterations determine the consequences of thesechanges? That is, what difference does it make if the calcium rise is lo-calized or widespread, whether it is near the cell membrane or at thenucleus or mitochondria? While these questions focus on the seeminglyfine details of calcium regulation, it is quite clear that the devil is, in-deed, in the details. Neuroplasticity and neuropathology are separatedby a hair.

III. Summary

Since this list of mechanisms covers much of what we know abouthow brain cells operate, one might object to using such a broad brushin characterizing a purportedly special feature of brain function--plas-ticity. But that is really just the point. If a significant aspect of brainfunction is plast icity, as I believe to be the case, then all (or at leastmost) brain mechanisms are like ly to be involved in plast ic processes.Indeed, we have identified very few special mechanisms associatedwith plasticity. Certainly, the factors that appear to be involved in epilep-tic pathologies are almost all old friends from the plast icity literature.It is this crit ical interrelationship between plast icity and pathologythat was so important in Frank Morre lls work, a concept he advancedat a time when our understanding of these mechanisms was far less so-phisticated than it is now. The influence of this idea is now pervasive inthe neuroscience field, so much so that it is hard to imagine why therewas so much resistance to these hypotheses when first advanced byMorrell. It is this general concept of plasticity-pathology relationshipthat will survive as the most influential legacy of Frank Morrell.

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1 Mechanisms of Brain Plasticity From Normal Brain Function to Pathology

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