)

20-'2..S". b'.

1~C;j3

NONLINEAR IN

MECHANISM MICROTUBULF;}S; INFORMATION SIGNALING AND

Tuszyriski of Alberta, University Sciences, Scienc~s,

OF

DIPOLE

DYNAMICS

IMPLICATION PROCESSING, ASSEMBLY

3, R.B. Canada Tuscon, Arizona, USA Vinca, Yugoslavia Zakala 4 Novi Sad,. Yugoslavia

FOR

M. V. Sataric 1Faculty 3 Department

1, J.A.

2, S. Hameroff Edmonton, of Arizona, Beograd,

of Technical

2 University of Anesthesiology, of Nuclear 4 Institute

Abstract Interiors of living cells are structurally and dynamically organized by networks of protein polymers called cytoskeleton. Of these filamentous structures micro tubules are the best characterized and appear to be most fundamental. Some evidence links the cytoskeleton with information processing and cognitive function. In this paper we address the question of how some functions of micro tubules may be related to the ground state properties of the lattice of dipoles. In general, three kinds of geometrical arrangements of dipoles are found: (a) random, (b) ferroelectric and ( c) spin-glass types. Each of these arrangements may exist under different conditions of temperature, electric field and microtubule length. The ferroelectric state appears most suitable for assembly and signaling processes whUe the spin glass state is ideally suited for information processing.

Introduction

1Ilteriors of living cells are structurally organized by networks of protein polymers called the cytoskeleton. Of these filamentous structures which include a-ctin and intermediate filaments, microtubules (MT's) are the best characterized and appear to be the most fundamental (Dustin, 1984). MT's are hollow cylinders 2.5 nanometers (nro) in diameter whose lengths may span macroscopic dimensions. MT's are assemblies of 13 longitudinal protofilaments, each of which is a series of subunit proteins known ~ tubulin (Figu.re 1). Each tubulin subunit is a ~olar, 8 nro-long dimmerwhich consists of two slightly different 4 nm:.long monomers, each with a molecular weight of 55 kilodaltons. These two constituent parts are referred to as Q and 13 tubulin. Each dimmerhas a net mobile electronegative cha-rge due to an abundance of acidic arnino acids, and binds 18 calcium ions. The net negative mobile charge is localized predomina-ntly towards the Q monomer so that each tubulin dimmer bears an oriented dipole. Thus, MT's are an example of an electret substance, i.e., an assembly of oriented dipoles. In this paper we investigate the types of spatial arrangements of these dipoles in detail and their implications on MT behavior.

NEURONET'93

-+E

.1 1 11 1 8 7 4

tp
-t-: ;.p

T RO

-L

.
Figure 1.
An Illustration of the microtubular arrangement.

Conformational states of tubulin dimmers present within MT's have been suggested to be coupled to charge or dipolar states, thereby allowing for cooperative interactions with neighboring tubulin dimmer sites (Hameroff, 1987; Rasmussen et al, 1990; Hameroff and Watt, 1982). This coupling would also lead to the presence of piezoelectric properties which are very common in ferroelectrics which, in turn, could prove very important in MT signaling, communication and assembly /disassembly behavior (Athensteadt, 1974; Margulis et al, 1978). MT associated proteins (M.I\.Ps) which may be structural, contractile or enzymatic are attached to MT's at specific tubulin dimmer sites and can link MT's with other MT's, 9ther parallel arrayed cytoskeletal elements, membranes and organelles to form networks and scaffolding within living cells. Some evidence links the cytoskeleton ',,:,ithinformation processing and cognitive function. For example; Mileusnic et al (1980) correlated production of MT subunit protein ("~ubulin") and MT activities with peak learning, memory and experience in baby chick brains. Cronley-Dillon et al (1974) showed that when baby rats begin their critical learning phase for the visual system (when they first open their eyes), neurons in the visual cortex begin producing vast quantities of tubulin. Tubulifi,production is drastically reduced when the critical learning phase is over (when the rats are 35 days old). Moshkov et al (1992) showed structural and chemical changes in goldfish brain neuronal cytoskeleton..following sensory stimulation. In gerbils e.xposed to cerebral ischemia, K udo et al ( 1990) correlated the amount of reduction in dendritic MAP2 with the degree of cognitive impajrment. Bensimon and Chernat (1991) found that selective destruction of brain MT's by the drug colchicine caused cognitive defects in learning and memory which mimic the clinical symptoms of Alzheimer's disea"!;e, which the cytoskeleton becomes entangled. Geerts in et al (1992) showed that sabeluzole, a memory-enhancing drug, increases fast axoplasmic transport. Matsuyama and Jarvik (1989) have proposed that Alzheimer's is a disease of MT and MAPs. In specific hippocampal regions of the brains of schizophrenic patients, Arnold et al (1991) fourid distorted neuronal architecture due to a lack of2 MAPs (MAP-2 and MAP-5).

\
2

1~

NEURONET'93

Models of learning in mammalian NMDA (n-roethyl-d-aspartate) hippocampal neurons (i.e. long term potentiation: "LTP" ) involve pre- and post-synaptic enhancement of synaptic function. Silva et al (1992) have shown calcilim-calmodulin kinase to be essential for LTP. Aszodi et al (1991) have demonstrated protein kinase A to be involved in learning. Halpain and Greengard (1990) have shown "that post-synaptic activation ofNMDA receptors induces rapid depho;sphorylation of dendrite-specific MAP2. Aoki and Siekevitz (1988) linked learning to protein kinase C mediated MAP2 phosphorylation/dephosphorylation, and Thelirkalif and Vallee (1983) demonstrated that MAP2 phosphorylation/dephosphorylation consumed a huge proportion of brain biochemical energy. Bigot and Hunt (1990) showed that NMDA and other excitatory amino acid neurotransmitters caused redistribution of intraneuronal MAPs, and Wang and Rasenick (1991) have shown that G proteins directly link with MT's. Surridge and Burns (1992) demonstrated that the lipid second messenger phosphatidylinositol binds specifically to MAP2, a coupling which may "constitute a link by which extracel1ularjactors influence the microtubule cytoskeleton". Kwak alld Matus (1988) showed that denervation caused long-lasting changes in MAP distribution, and Oesmond and Levy ( 1988) showed that LTP involved cytoskeletal-roediated shape changes in dendritic spines. Lynch and Baudry ( 1987) have proposed that proteolytic digestion of the sub-synaptic cytoskeleton, followed by its structural reorganization, correlate with learning and Friedrich (1990) has formalized a learning model of synaptic cytoskeletal restructuring. Synaptic regulation, both in learning and steady state, also depends on material (enzymes, receptors, neurotransmitters, etc:) synthesized in the cell body and transported along ax9ns and dendrites by contractile MAPs attached to MT ("axoplasmic transport"). Similar mechanisms involving, actin, synapsin, and other cytoskeletal polymers are involved in neurotransmitter release. Further suggestion for cytoskeletal computation and/or information storage stems from the spatial distribution of discrete sites ( or states) in the cytoskeleton. For example, tlibulin subunits in closely arrayed MT have a density of about 1017 per cm3, which is very close to the theoretical limit for charge separation (Gutroan1L, 1986). Thus cytaskeletal polymers have maximal density for information representation by charge, and the capacity for dynamically coupling that information to mechanical and chemical events via cooperative dipole states.

The

dipolar

lattice

and

spin-glass

phase

Our baSic premise physically views the entire MT as a regular array of coupled local dipole states which iJlteract with their immediate neighbors. Although tubulin undergoes conformational changes (e.g. Melki et al, 1989), we a;dopt a simplified view in which elastic degrees of freedom are not explicitly included in the description. We will return to this question in the Discussion. The starting point in the analysis is to adopt a hexagonal lattice structure with the dimensions and orientations observed by X-ray diffraction of MT and shown in Fig. 2. Each lattice site is assumed to possess a dipole moment p = Q .d where Q = 2e and d ~ 4 nm whose projections on the vertical a-Xis can only be +p or -p. The interaction energy between two neighboring lattice sites is
Hij = /

3 COS2(J -1 3 r. .
'3

2 p

(2.1)

where 0 is the vacuum permitivitty and Tij is the distance between sites i and j. The angle O is between the dipole axis and the direction between the two dipoles. Fig. 2 illustrates the situation resulting from our calculations; .
3

NEURONET'93

(a)

(b}

Figure 2. A tubulin dimmer and i ts nearest neighbors. ( a) Exchange constants (b) and their signs ( c) within a unit hexagonal cell ( c). ( d ) A band of hexagons spanning the circumference of a microtubule. In Fig. 2c the signs" + " and" -" refer to dipole-dipole interactions that prefer either a parallel or Below, we present the numerical results for

antiparallel arrangements of dipole moments, respectively. the constant J1, J2, J3 and the corresponding angles,
]1 = 5.77.10-21] ]2 = -0.71.10-21] ]3 = 3.40 .10-21 ]

el = 00 e2 = 58.2 e3 = 45.6. Ising model on a triangular

We can, therefore, map this situation as an anisotropic two-dimensional lattice so that the effective Hamiltonian is
H = -'\:""""'

L.., <nn>

J.

tJ

S .Z S~
t J

(2.2)

and the effective spin variable Si = :!:1 denotes the dipole's projection on the vertical axis. The exchange constants ]ij take the values ]1, ]2, ]3, depending on the choice of dipole pairs. What, therefore, appears in Fig. 2b is that the system exhibits frustration (Suzuki, 1977) in its ground state. This means that for any closed path it is impossible to satisfy all bond requirements. Hence, there will al ways be a conflict between satisfying the energetical requirements of .', + " bonds and " -" bonds. The ensuing phase structure is known in the physicalllterature as a spin-glass phase (Fischer, 1983; 1985). In a spin glass (SG ), spin orientations are locally "frozen" in random directions due to the fact that the ground state has a multitude of equivalent orientations. For example, for each triangle reversing the spin on one side with respect to the remaining two leads to an equivalent configuration. Having the number of triangles on the order of the number of lattice sites N "' 2 .104 yields the degeneracy of the
4

'C;;1..

).

NEURONET'93

ground state on the order of 6N which is a very large number! (namely"", lO1S,OOO) This is schematically shown in Fig. 3.

Figure 3.

A schematic

representation

of the energy dependence on co:nformationa.l

states.

Small potential barriers separating the various equivalent arrangements of spins play another useful role. Relaxation times are very long for the various accessible states giving them long-term stability. Some other properties of the spin glass phase are: ( a) absence of long-range order between spin sites; (b ) the presence ofshort-range correlations This means that the system is very "soft" energetically permitting a number of spin arrangements which are relatively stable. However, there is no tendency towards the formation of large correlated spin clusters. Thus, a spin glass phase exists near a transition to chaos. LaJIgton (1990) has shown that such a quality is optimal for computational applications as discussed by Lcwin (1992). Spin glass phases also allow easy formation of local ordered states, each. of which carries an information content and is long-lived, i.e. relatively stable over time. On the other hand, it is not difficult to switch from one state to another ( e.g. f-rom spin-glass to ferroelectric) through various physical means. 'rhis can be achieved by: (a) an application of an electric fieln along the axis. We estima.te that intracellular fields on the order of 104 V /m are sufficient to switch an MTfrom a spin glass to a ferroelectric state (F). (Note that fields up to 107 V /m are known to exist across cell membranes). (b) Raising the temperature above the spin-glass transitioRtemperature will drive the system to a disordered (paraelectric) phase. ( c) A spin-glass is also sensitive to boundary conditions. This means, for example, that the presence of domain walls will reduce the effective size of a correlated cluster and this will have a profound effect on the SG phase. As will be discussed in the next section, domain walls may easily form in a microtubule under specific conditions. We mentioned above that another ordered phase is favored when a moderate external field is applied ( or indeed when the temperature is lowered further ). This phase, called a ferroelectric phase, is characterized by long-range order manifested by an alignment of spin directions along the axis. This is shown in Fig. 4. Obviously, from the point of view of optimal information content, this is ll.Q1 a very useful phase. However, the ferroelectric phase can playa major role in signaling and the assembly / disassembly processes. This will be discussed at lenght in the next Section. Before we discuss this aspect, we investigate its general properties. The ferroele<;tric phase can also be destabilized by temperature when T exceeds Tc. To obtain a crude estimate of Tc we approximated the MT by aR infinite triangular lattice with the exchange constants 11,!2 and ]3 given above and ?sed the formula (Domb, 1960).
SI. 11 h( l.' 211 "1' .l\.B.LC

) SI. n h(

"l.' 212"1'.l\.B.LC

.2J1 + SIll h( -r::--;:r;l(B.LC

.2J3 ) Sill h( ~ l\.B.LC

s~n

' h(

7:...

2}2 ;j:;

) Sill h ( .

~)=1.
.I{B.LC

7:.

rro

(2.3)

.I1.B.LC

(,-,

NEURONET'93

.E

f f

T < Tc

The dipole orientations in the ferroelectric state. . The result we obtajned is Tc ~ 402 K for the charge of q = 2e, the permitivity E: = io and the dipole displacement d = 4 nm. Takjng q = le, E:= 5 and d = 4 nm yields Tc = 201 K. This very rough estimate of Tc indicates nevertheless that an interesting phase behavior can be expected in the physiological temperature range around 300 K. In addition, it js well known that the size of a lattice affects Tc greatly. In general, for size N, T c( N) is related to that for an infinite lattice T c( 00) through (Binder et al, 1985). r~igure 4.
(2.4)

where a is, an approximate proportionality coefficient and l' is the correlation length exponent ( typically close to 1/2). Thus, for a.finite-size lattice the transition temperature is expected to be less than that for an infinite lattice. In other words, dipole ordering is more likely to occur when a critical size of the MT is achieved. In addition, other important factors may affect the value of Tc and thus provide sensitive control mechanisms. Through a coupling to the elastic degrees of freedom (conformational change), the value of Tc may be shifted. The dielectric constant may be altered by the presence of water molecules surrounding an MT structure. This would decrease the value of T c and introduce disorder. Small changes in the angles between the dimer dipoles may remove the frustration mechanism effectively preventing the onset o(the SG phase. Changes in the opposite direction can enhance frustration favoring the SG over the F phase and effectively switching from the growth mode of operation to an information processing behavior. Thus symmetry transitions or mechanical forces may effect switching between phases. Once in the [erroelectric phase, the system is also very sensitive to the frequency of electromagnetic oscillations. It is known that in organic ferroelectric materials a resonant frequell;cy exists Wo which is inversely proportional to the length, stiffness constant and the square root of the density (Matthias, 1973). Extrapolating the data given by Matthias (1973) one finds for microtubules a resonant frequency range exceeding 108 Hz and thus being rather close to the microwave range predicted by Frohlich (1980) to playa major role in living cells. In Figure 5 we have shown the results of our Monte Carlo computations intended to reveal the size dependence of the phase behavior discussed above. Figure 5a) is a plot of the mean polarization per site when the microtubule is composed of only 26 layers (i.e. it is a 13 x 26 lattice) it is clear that three distinct ranges exist: ( a) the low- temperature ferroelectric range, (b) the intermediate spin-glass range and ( c) the high-temperature paraelectric'"fange. Figure 5b) illustrates the same dependence for a microtubule with 5000 layers (i.e. it is a 13 x 5000 lattice). We conclude that the intermediate spin-glass phase all but disappeared.
6

NEURONET'93

Mean

Polarization

Per

Site

Moon

Pol81"iz8lion

POI" Site

1.0

t[

0.8

.,

0.61 0.41 i

0.21 0., 200

300

400 T(K)

Figure

.5

A plot of the mean polarization

persite for a triangular lattice whose size is a) 13 x 26 and b) 13 x 5000.

FerrQelectricity,

signaling

and

assembly

/disassembly

It is well known that ferroelectrics are on~ of the few types of materials whose description is most ~dequately provided in terms of mean field models (Kretschmer and Binder, 1979). A typical approach is to postulate a double-well quarticon-site potential V(Sn) that gives the overall effect of the environm~nt on a selected dipole site n. Thus, V(Sn) = -~AS~+ lBS~ (3.1)

where Sn is the effective spin variable at site n and the coefficients A ~nd B are model dependent. It will be subsequently assumed that over long distances the variable Sn cha:ngesvery gradu~y and can be treated as a continuous variable. In the F -phase, the MT cylinder taken as a whole represents a giant dipole. When the cross-section of a MT is viewed using electron microscopy, the outer surfaces of a MT are surrounded by a "clear zone" of several nm which apparently represents the oriented molecules of cytoplasmic water and enzymes (Stebbings and Hunt, 1982). This could be explained by the presence of an electric field produced by a MT. Therefore, we assume that together with the polarized water surrounding it, a MT generates a nearly uniform intrinsic electric field parallel to its axis (see Fig. 1). Consequently, the additional potential energy due to this electric field and associated with each dIpole is
Vel = -CSn, .C = qE (3.2)

where q denotes the effective cha.rge of a "single dimer and E is the magnitude of the intrinsic electric field. Within this picture, the model Hamiltonian for the dipole moments of a microtubule can be written as {3.3} The first term above represents the kinetic energy associated with the longitudinal displacements of constituent dimmerseach of which has mass M. The second term arises from the restoring strain forces between adjacent dimmers the protofilament. 1f the stiffness parameter K is sufficiently Jarge, then it in is expected that large-amplitude long-wave length excitations of the displacement field will be formed manifested by a slowly varying modulation of Sn along the MT axis.
7

NEURONET'93

In order to derive a realistic equation of motion for this system, the viscosity of the solvent is indispensable and the associated damping force must be introduced. Assuming for simplicity that the solvent is made up of only water molecules we may infer that water will provide a viscous medium that will damp out vibrations of dimmerdipoles, This can be taken 'into account by adding the viscous force to the equation of motion with F = -1'~ where l' is theda.mping coefficient. Based on our assumption that the dipolar oscillations of dimers within a MT form a system that can be classified as displacive ferrodistortive, we can use the continuum approximation to obtain the corresponding equation of motion as

Note that the x-coordinate is along the protofilament axis. Moreover, for longitudinal sound waves the dispersion relation I..J= ,jKJM can be used to identify the sound velocity with VO2 I..JRo= ,jKJMRo. = We now seek solutIons of eq. (3.4) in the traveling-wave form where the moving coordinate 0;is given
by

f. = [~]1/2(X with V denoting the propagation velocity

~ Vt) = a(x -Vt) and the coefficient

[
M(Vo2

(3.5)

a is, of course,

IAI
-V2)

1/2 ,

a-

Consequently, eq. (3.4) is reduced to the ordinary differential equation below

M Q2(V2 -VO2)S'I -/QV Sf ~ AS + BS3 -qE = 0.

(3.6)

Where S' = dS! df..This is an equation for an anharmonic oscillator with linear friction. For the sake of convenience we now introduce a normalized displacement field as: 'I/J(f.) = S(f.)! So where the normalizing coefficient So = vrxrm corresponds to the minimum of the double well potential in eq. (3.1). It has been shown by Collins et al (1979) that eq. (3.6) has a unique bounded solution which is given , by the formula ( and illustrated graphically in Fig. 6 (3.7)

Figure 6.
8

The function '!/J( at rest ( -) and moving at a terminal velocity V > O in the applied f.) electric field E( ...).

,--,-~~

-,

!;';;~;--,!

-c';

c7*-~~'"-'--'

NEURONET'93

where ,8 = (b -a)/J2

and the parameters a, b and d satisfy the cubic equation

( 'I/; -a )( 'I/; -b )( 'I/; -d) = '1/;3-'I/; -0"

(3.8)

where
0- = qVBrAI-3/2 Formula (3.7) describes a kink-like excitation (KLE) which E. takes the ,form of a domain propagates wall separating with

two distinct ferroelectric domains. It is also imp.ortant to note that the above kink-like a fixed velocity V -Vo which is ~ than the sound velocity
1[

soliton

along the protofilament

212 1 + 9d'iMV,'

] 1/2

(3.9) coefficient d. 1. It is

Vo and decreases with of the electric

an increase of the friction the parameter with E

clear that V depends on the magnitude

field E through

For T well below Tcl V can be approximated

by a linear relationship

where the coefficient of proportionality is called mobility and will be denoted by Jl. Using simple arguments from fluid dynamics, Jl can be estimated numerically as
J.L ~ 2 .lO-5m2V-1 S-1

Thus, for E = 105 Vm-l

we obta-in V ~ 2 m/s which can increase to 102 m/s close to the MT's ends to the other we estimate the average

where E increases dramatically. Assuming a smooth journey from one end of the protofilament time of propagation T for a single KLE to be

To summarize, we showed that a unique kink-like excitation exists in the ferroelectric phase which may propagate along a MT with a velocity that is proportional to the electric field E. KLE's in MT's which ate stable may constitute signals transducing membrane events via second messengers to other cell regions. Energy for such KLE's may come from GTP hydrolysis or phosphorylation via MAPs. In neurons, KLE's in MT's may signal error information retrograde (i.e. from axon to dendrite) which would be useful in synaptic regulation and learning as in artificial neural network "back-propagation". In MT's which are unstable (i.e. whose ends are not stabilized by MAPs or other structures), KLE's can explain the fact that growth rates are different at the two ends of a MT. To this end we assume that KLE formation is mainly due to the hydrolysis of GTP into GDP so that one act of hydrolysis corresponds to conformational change resulting in the formation of a single KLE. However, a KLE is preferentially oriented towards the direction of the intrinsic electric field. The propagation of a KLE will then distribute the energy of hydrolysis at the prefereed end ofa MT. This energy :may then be used to detach dimers from the MT. This picture is in accordance with a hypothesis put forward by Kirschner and Mitchi~on (1986) who stated that on-rate (growth) is limited in principle only by the rate of diffusion of the monomer subunits into MT polymers (i.e. by the concentration of the constituent monomers in solution). On the other hand, the off-rate ( depolymerization) can be extremely rapid and the net amount of MT polymer formed can be regulated independently by the hydrolysis of GTP.
9

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N~URONET'93

!
I i 1

It is reasonable to expect that at the onset of the MT assembly process, when MT's are very short, the formation of KLE's is very unlikely ( or even impossible ), since lor a short chain the displacement field gradient required would be very high and the associated energy to form it prohibitively large. However, when the length of a MT reaches a threshold value, kink propagation could become a real possibility. Excitation of kinks being related to GTP hydrolysis would become dependent on the GTP concentration. As MT's become longer, KLE propagation accelerates leading to a disassembly at the "-,, end. KLE propagation in stable MT's would depend on MAP phosphorylation or cytoplasmic kinase activity triggered by membrane events and second messengers.

Summary

References
[1] Aoki C; and Siekevitz P., Sci Am 34-42, 1988. , [2] Arnold S.E., Lee V .M. Y ., Gur R.E. and Trojanowski J .Q., Proc Natl Acad Sci 88:10850-10854) 1991. [3] AthenstaedtH., Ann. N.Y. Acad. Sci. ~, 68 (1974).

[4] Barnett M., in F. Carter (ed.), (Naval Research Laboratory) Washington) D.C., 1987). [5] Bensimon G. & Chernat R., Pharmacol Biochem Behavior38:141-145, [6] Bigot D. and Hunt S.P.) NeurosciLett 111:275-280,1990. 1498 (1985). 1991.

[7I Binder K., Nauenberg M.) Privman V. and Young A.P., Phys. Rev. B.~,

[8] Collins M.A., Elumen A., Currie J.F. and RossJ., Phys. Rev. EN, 3630 (1979).
[9] Cronly-Dillon
[10] Desmond N .L.

J ., Carden
and Levy

D. & Birks
W .B ., Long-

C., J Exp BioI 61:443-454,

~ Term Potentiation: From

1974.
Biophysics to Behavior, eds.

Landfield

and SA Deadwyler,

1988.

111] Domb D.., Phil.

Ma Suppl. .9.,35 (1960).

10

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[12] Dustin p;, Microtubules (Springer, Berlin, 1984). [13] Fischer K.H., Phys. Stat. Sol. (6) ill., 357 (1983).

[14] Fischer K.H., Phys. Stat. Sol. (6) liQ., 13 (1985). [15] Friedrich P., Neurosci 35:1-T, 1990. [16] Frohlich H., Adv. Electr. Electr. Phys. ~, 85 (1980). [17] Geerts H., Nuydens R., Cornelissen F., De Brabander M., Pauwels P., Janssen P.A.J., Song Y.H. and Mandelkow E.M., Experimental Neurology 117:36-43,1992. [18] Gutmann F., Mode!E Bioelectrochemistry) 177-197,1986. [19] Halpain S. and Greengard P.. Neuron 5:237-246, 1990. 120] Hameroff S., Ultimate Computing (Elsevier North-Holland, [21] Hameroff S.R., Dayhoff J .E., Lahoz-Beltra 25(11),30-39,1992. [22] Hameroff S.R. and Watt R.C., J. Theor. Biol. ~, 549 (1982). [23] Horio T. and Hotani H., Nature m, 605 (1986). Amsterdam, 1987). Computer eds, F. Gutmann & H. Keyzer, Plenum Press, New York,

R., Samsonovich A., Rasmussen S., IEEE

[24] Kretschmer K. and Binder K., Z. Phys. B. M, 375 (1979). [25] Kudo T., Tada K., Takeda M. and Nishimura T., Stro.ke 21:1205-1209, 1990 [26] Kwak S. and Matus A., J Neurocytol17:189-195, 1988.

[27] Lynch G. and Baudry M., Brain Res Bull 18:809-815, 1987. [28] Margulis L., To L. and Chase D., Science 2JlQ, 1118 (1978). [29] Matsuyama S.S. & Jarvik L.F ., Proc Nat Acad Sci 86:8152-8156, 1989. [30] Matthias B.T ., in Proceedings of the Third International Biology", pp. 12-20 (Karger, Basel, 1973). [31] Melki R., Carlier M.F., Pantaloni D. and Timasheff S.N., Biochem. 2.8.,9143 (1989). [32] Mileusnic R., Rose S.P. & Ti1lson P., Neur Chem 34:1007-1015, 1980. [33] Mithieux G., Chauvin F ., Roux B. and Rousset B., Biophysical Chem 22,307-316 (1985). Conference "From Theoretical Physics to

[34] Moshkov D.A., 8a.valjeva.L.N ., Ya.njushina. G. V .,Funtikov V .A., Acta Histochemica Suppl-Band XLI, 8:241-247,1992. [35] Rasmussen S., Karampurwala (1990).
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H., Vaidyanath R., Jensen K. and Hameroff S.R:, Physicia D .4;..2.,428

Wehner J.M. and Tonegawa

S., Science 257:206..211,1992.

11