Neural Mechanisms

Living with FAS

The fetal brain is most susceptible to the neurotoxic effects of ethanol during the third-trimester synaptogenesis, which is also known as the “brain growth spurt”[1]. Although the placenta is supposed to act as a barrier against certain substances for the protection of the fetus, it exceptionally allows the crossing of ethanol[2][3]. As the development of the fetus has yet to reach the stage at which ethanol detoxicating agents, such as ADH enzymes are expressed within the liver, the fetus will be subjected to lengthy intrauterine exposure to ethanol should the mother chooses to consume alcohol[3].

Growing evidence suggests that ephemeral exposure of the developing brain to ethanol potentially induces detrimental apoptosis of neurons, and thus dysmorphogenic anomalies and neurobehavioral dysfunctions observed in Fetal Alcohol Syndrome (FAS)[4]. Apoptotic neurodegeneration is widely distributed among the general brain mass, including the auditory and visual cortices[5]; it is however specifically localized at the cerebellum and hippocampus. The thorough destruction of neuronal and synaptic circuits therefore results in the interference of not only the integration of sensory information, but also fundamental behaviors and functions, such as memory and motor skills[4]. Despite the extensive research conducted on FAS, no candidate neuronal or biochemical pathway can be designated as the definitive mechanism underlying its development. Nevertheless, animal models, especially rat and mice models, have provided critical and fairly compelling clues as to how ethanol stimulates apoptosis and the impairment of synaptic plasticity[1][4]. It is essential to have continuous investigation on the neurodegenerative aspect of FAS, as further research may provide valuable insight on targeting specific molecular pathways for developing potential therapeutic strategies and treatments that are lacking today.

1.Apoptotic Neurodegeneration

1.1 Dual Mechanism

1.1a Blockade of NMDA Receptors

Ethanol-induced apoptotic neurodegeneration
Image Unavailable
Silver staining was done on ethanol (top)- and
saline (bottom)-treated mice during synaptogenesis.
Cell death represented by black dots was much more
extensive in the ethanol-treated than the saline-treated mice.
Image source: Olney, J.W. et al., 2001.

Glutamate is the major excitatory amino acid that is involved in the neurotransmission between numerous components within the central nervous system (CNS) as well as synaptic plasticity that is important for certain behaviors[6][7]. Prenatal synaptogenesis, which spans the last third trimester during pregnancy, marks the critical period for neuronal growth and the fine turning of synaptic connections that are largely dependent on the N-methyl D-aspartate (NMDA) receptor-mediated glutamatergic actions[1][4]. Normally, glutamate influx through the postsynaptic AMPA receptors causes the removal of the extracellular Mg2+ block on NMDA receptors, and stimulates their activation. Subsequently, induced long-term potentiation (LTP) leads to the strengthening of synapses, and contributes to the output of certain behaviors, such as learning and memory. However, if NMDA receptors are blocked, neuronal plasticity and activity will be substantially suppressed[8]. The abnormal reduction in neuronal excitability induces an intracellular self-killing program that resembles the programmed cell death (PCD), hence resulting in the large-scale loss of neurons[5].

Since ethanol has known NMDA receptor antagonist properties, many studies have investigated the potential of ethanol in triggering apoptotic neurodegeneration in mammalian infant brains[5]. Typically, these studies involve treating two groups of mice or rats, namely the control and treatment groups, with saline and NMDA receptor antagonists, respectively. With the use of silver staining, histological analysis on the pattern of neuron degeneration can be made[4]. Saline-treated animal brains generally show very little apoptotic pattern, which can be attributed to normal PCD that disposes infected or physiologically superfluous cells[4][9]. On the contrary, animals treated with ethanol and other NMDA receptor antagonists, such as MK-801 and phenobarb, often show generalized widespread fragmentation and death of cells within the brain. While the administration of ethanol, MK-801 and phenobarb all influence the apoptosis of neurons localized in the cortical surface of the developing brain, ethanol treatment particularly results in the elimination of neurons within the middle and deep layers of the cortices as well. Therefore, ethanol appears to have greater potency than the other NMDA receptor antagonists in causing cell death[4]. Ethanol-mediated blockade of glutamatergic actions and the subsequent loss of intracellular excitation is specific for NMDA receptors, since apoptotic neurodegeneration is not observed when other excitatory receptors, such as muscarinic and kainate receptors are inhibited[7].

1.1b Hyperactivation of GABAA Receptors

Ethanol disrupts the appropriate balance between excitatory and inhibitory signals within the CNS in different ways. In FAS studies, the observation of neuronal loss in areas that are not typically under the control of NMDA receptors led to the hypothesis that perhaps other major neurotransmitter-mediated networks within the brain are also altered by the transient exposure to ethanol[4][7]. Since γ-aminobutyric acid (GABA) is the major inhibitory amino acid in the CNS, a reasonable postulation would be that the increase in the extracellular levels of GABA or the hyperactivity of their respective receptors, the GABA receptors, may contribute to the ethanol-induced cell death. Indeed, an elevation of GABA levels in fetal rat brains exposed to ethanol has been observed in several studies[10]. As for the receptors, it was found that out of the various types of GABA receptors, GABAA receptors are the ones that implicate the development of FAS.

GABAA receptors are ionotopic receptors within the family of ligand-gated chloride ion (Cl-) channels. As GABA binds to GABAA receptors, Cl- channels open and allow the influx of Cl- down its concentration gradient into the cells[11]. Growing evidence suggests that apoptotic neurodegeneration occurs as ethanol triggers the over excitation of GABAA receptors, resulting in the excessive influx of Cl-, and thereby the hyperpolarization of neurons[12]. The inhibition of depolarization correspondingly reinforces the inhibition of calcium ion (Ca2+) release from the sarcoplasmic reticulum, and in turn causes the depressing of cytosolic Ca2+ [13]. Though the details of the biochemical sequence through which neuronal death is initiated is unclear, abnormal reduction in intracellular excitability during the critical period of synaptogenesis is inevitably deleterious and is responsible for increasing the susceptibility of cells to apoptosis[5].

Studies showed that ethanol-induced apoptosis could be significantly prevented if extracellular potassium ions (K+) or intracellular Ca2+ are elevated[13]. This finding further confirms that it is the suppression of neuronal activity that initiates an internal signal to influence cells to commit suicide. It also provides insight in the development of possible therapeutic treatment that targets specific molecules or receptors in order to maintain a healthy balance between excitation and inhibition within the CNS. Furthermore, many studies have tested the potential of GABAA receptor agonists, which mimic or enhance the actions of GABA, in triggering apoptosis in FAS. In addition to ethanol, common GABAergic agents, such as phenobarbital and benzodiazepines also show competence in promoting cell death and the destruction of brain structures[4][13]. Therefore, pregnant individuals should be advised to avoid the prolonged use of these pharmaceutical drugs, so as to prevent the fetal risk of developing FAS.

1.2 Apoptotic Pathway

Intrinsic and extrinsic apoptosis
Ethanol-induced apoptosis is mediated by the intrinsic pathway.

Two pathways have been described through which apoptosis occurs, namely the intrinsic and extrinsic pathways. Both pathways result in the eventual activation of caspase-3, which is a cysteine-aspartic acid protease that triggers cell apoptosis. However, the extrinsic pathway involves the antecedent activation of caspase-8, whereas the intrinsic pathway does not involve the participation of this particular caspase[1].

1.2a Intrinsic Pathway

Following ethanol administration to fetal animal models, the suppression of neuronal activity initiates a death stimulus that influences the translocation of Bcl-2-associated X (BAX) protein from the cytosol to the outer mitochondrial membrane[1]. The BAX protein increases the membrane permeability, and allows the influx of a combination of ions. This results in the efflux of cytochrome C into the cytosol through means that remain to be elucidated[14]. The released cytochrome C then binds to the apoptotic protease activating factor-1 (Apaf-1), which in turn activates the caspase cascade. It begins with the cleavage of inactive procaspase-9 to form active caspase-9, which subsequently cleaves the inactive procaspase-3[15]. The resulting active caspase-3 will then target and attack the developing neurons within the fetal brain. The compression and separation of the chromatin, as well as the condensation of the cytoplasm lead to the fragmentation of cells into apoptotic bodies. They will ultimately be detected and engulfed by surveilling phagocytes[16][17].

While ethanol-treated wildtype and heterozygous bax+/- mice models displayed extensive distribution of caspase-3 and an absence of caspase-8 in brain structures, genetically modified knockout mice bax-/- showed absence of caspase 3 and ethanol-induced cell death[16]. In short, the intrinsic BAX-mediated mitochondrial pathway, rather than the extrinsic death receptor pathway, is the underlying mechanism through which ethanol causes apoptotic neurodegeneration in FAS mice[5].

1.3 Determinants of Vulnerability

The specific determinants for the susceptibility of offspring to developing FAS are highly controversial within the research field. In fact, the definitive threshold level of alcohol consumption safe for pregnancy has yet been determined. However, strong evidence has suggested that the interplay between the time window, dose and duration of fetal brain exposure to ethanol is crucial in estimating the relative risk of FAS[18].

Time window of vulnerability
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Ethanol-induced apoptotic neurodegeneration
mostly occurs between developmental ages E19 to P14.
Image source: Ikonomidou, C. et al., 2000.

1.3a Time Window

Animal studies have provided valuable information on the timing of ethanol exposure during pregnancy that may significantly interfere with critical fetal synaptogenesis, and thereby increase the vulnerability to FAS. In rat models, it was observed that apoptotic neurodegeneration induced by the dual mechanism of NMDA receptor blockade and GABAA receptor hyperactivation occurred between the embryonic stage E19 and the postnatal stage P14[4]. This period not only coincides with the synaptogenesis phase in rat neurodevelopment, but it also corresponds to the human brain growth spurt, which spans the last trimester of gestation[4][5]. This finding thus suggests that transient intrauterine exposure to ethanol within this particular time window kills millions of neurons and causes severe loss of brain mass.

1.3b Dose of Ethanol

To date, there is no definitive threshold for safe consumption of alcohol for pregnant individuals. There is also rigorous debate on whether there is a correlation between the specific dose and the risk of FAS[18]. In a human study on the effects of prenatal exposure to ethanol, dose-dependent loss of neurons and dysmorphogenic consequences were observed[19]. Also, in a rat model, fetal rats administered with a sudden higher-than-usual dose of ethanol during synaptogenesis exhibited greater susceptibility to experiencing apoptotic neurodegeneration than fetal rats that were consistently infused with a constant dose of ethanol. This finding hence demonstrates that the sudden surge of blood ethanol level, rather than the stable exposure to a constant dose of ethanol, is one of the key risk factors of FAS[[20].

1.3c Duration of Exposure

On the contrary, certain studies have disagreed with the dose response explanation for the destruction of neurons in FAS. Specifically, these studies suggest that it is the duration of exposure, yet not the dose, that mediates the deleterious effects of ethanol on fetuses. In particular, one of the studies postulated 200mg/dl ethanol as the safety threshold for mother alcohol consumption. The authors of this investigation concluded that ethanol intake and the exposure of fetal brain to its neurotoxic effects above 200mg/dl for a period of 4 hours or longer significantly amplified the lethal apoptosis of neurons. A close correlation between the progression of cell death and the duration of which ethanol intake is elevated above the safety threshold has therefore been suggested[4].

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2. Alteration of Synaptic Plasticity

2.1 Cerebellar Reversal of Plasticity

The cerebellum is one of the main areas that is highly susceptible to and can experience very prominent damage from ethanol exposure, especially during prenatal neurodevelopment. This explains why FAS patients often exhibit anomalies in motor skills and gait[4]. Ethanol administration not only subject cerebellar Purkinje cells to potential apoptosis, but it can also cause the reversal of synaptic plasticity within these cells, resulting in severe alterations in motor learning[4][21]. As Purkinje cells constitute the integration center for incoming motor information, and are responsible for producing the key and sole output of motor activities, it is crucial to study the underlying neural mechanisms through which ethanol impairs the fine and gross motor skills in FAS[21].

2.1a Climbing and Parallel Fibers

Long-term depression (LTD) and long-term potentiation (LTP) have enormous implications on motor learning mediated by certain fibers within the cerebellum. LTD and LTP induced within climbing fibers (CF) and parallel fibers (PF) synapse and stimulate the Purkinje cells, and thereby regulate their firing rate[21][22]. Normally, the coactivation of CF and PF results in the induction of LTD, which is important for coordinating motor outputs from the cerebellum[23]. However, different studies have demonstrated that ethanol tends to inhibit LTD induction in both CF and PF[22]. Without the necessary inhibitory control on neurotransmission and synaptic connections, LTP will be significantly enhanced within the PF. The abnormally strengthened parallel fiber-Purkinje cell synaptic plasticity consequently raises the firing rate of Purkinje cells and causes undisciplined motor outputs within the CNS[21].

2.1b Inhibition of mGluR1

Motor learning in the cerebellum
Image Unavailable
In FAS, this mechanism is disrupted due to
the inhibition of mGluR1 by ethanol. LTD is reversed to LTP.
Image source: quizlet.com

mGluR1 is a member of the G protein-coupled glutamate receptor family that is involved in the tight supervision over proper neural communication and synaptic plasticity. This receptor is present on PF, which synapse onto Purkinje cells[24]. In standard conditions, the activation of mGluR1 produces slow metabotropic currents, and in turn initiates downstream intracellular signal transduction cascades for the production of LTD[25]. However, ethanol has negative implications on mGluR1, as it blocks mGluR1 and impedes LTD induction. The effect of ethanol on hindering LTD production is specific for mGluR1, since it is commonly agreed that mGluR1 regulates LTD, yet not LTP induction. Also, it has been shown that the basal firing activity of PF is not affected by ethanol, and thus rejecting AMPA receptors as candidates that play a role in motor discoordination[22]. Some researchers that studied knockout mGluR1-/- mice observed that the substantially promoted ataxia, tremor and other motor defects resulted from the genetic modification[26][27]. Another example confirming the significance of mGluR1 is provided by studies done on paraneoplastic cerebellar ataxia, a disease that involves the generation of autoantibodies that attack and eliminate GluR1. These individuals all suffer from acute motor abnormalities as a result of the inability of inducing LTD within the cerebellar fibers[28].

2.1c Inactivation of VGCC

The activation of mGluR1 within PF is essential for eliciting downstream signaling pathways and the eventual induction of LTD. The cascade begins as inositol triphosphate (IP3) is produced within the cytosol. The released IP3 binds to IP3-gated Ca2+ channels present on the endoplasmic reticulum, and mediates the efflux of Ca2+ into the intracellular space[29]. The increased Ca2+ level then activates the gamma isotope of protein kinase C (PKC-γ), which in turn phosphorylates voltage-gated Ca2+ channels (VGCC) localized in the neuronal membranes in order to further trigger influx of Ca2+ [21][30]. This is because when compared to LTP, the induction of LTD has a much higher Ca2+ threshold requirement. However, since ethanol blocks the activation of mGluR1, the expression of PKC-γ subsequently decreases. The resultant inactivation of VGCC, and thus the limited levels of intracellular Ca2+, causes reversal of synaptic plasticity, and hence aberrant cerebellum output. A plausible future therapeutic target is then the facilitation of PKC-γ activation with specialized biochemical agents, such as phorbol 12, 13-diacetate (PDA), so as to reinforce the elevation and recovery of a VGCC current for preventing or treating FAS[21].

2.2 Hippocampal Impairment of Plasticity

The hippocampus is an important brain structure for some vital behaviors, such as memory and learning[31]. Yet, it is one of the major targets for ethanol damage during synaptogenesis and the maturation of circuits[32]. Animal studies show that prenatal exposure to ethanol during the first and second trimester equivalents may lead to disruption of certain functions of the hippocampus, for example, poor short-term memory. However, transplacental exposure to ethanol during the third trimester equivalent can produce life-long permanent memory and learning disabilities, which are commonly observed in FAS patients[33].

Since ethanol has been previously described as having an inhibitory action on the excitatory NMDA receptors, it was once postulated that ethanol causes hippocampal CA1 region alterations through eliminating NMDA-mediated synaptic plasticity[34]. Yet, this hypothesis is unlikely and has been disagreed by several studies. Instead of affecting the induction phase by reducing the amount of presynaptic release of glutamate and blocking the formation of LTP, ethanol affects the expression and maintenance phases of LTP[33]. Specifically, studies have suggested that the interference with the action of protein kinase A (PKA) may play an important role in impairing synaptic plasticity[35][36]. This is because ethanol reportedly has an inhibitory effect on the signaling actions of PKA[37]. Also, PKA is vital for the maintenance of LTP[38]. Therefore, further investigation on the effect of ethanol on PKA should be conducted. This enzyme may be a potential key target of ethanol in causing the devastating untreatable FAS.

Bibliography
1. Medina, A.E. (2011). Fetal Alcohol Spectrum Disorders and abnormal neuronal plasticity. Neuroscientist, 17(3): 274-87.
2. Nava-Ocampo, A.A., Velazquez-Armenta, Y., Brien, J.F., & Koren, G. (2004). Elimination kinetics of ethanol in pregnant women. Reproductive Toxicology, 18: 613-7.
3. Zelner, I., & Koren, G. (2013). Pharmacokinetics of ethanol in the maternal-fetal unit. J Popul Ther Clin Pharmacol, 20(3): e259-65.
4. Ikonomidou, C., Bittigau, P., Ishimaru, M.J., Wozniak, D.F., Koch, C., Genz, K.,…Olney, J.W. (2000). Ethanol-induced apoptotic neurodegeneration and fetal alcohol syndrome. Science, 287: 1056-60.
5. Olney, J.W. (2004). Fetal alcohol syndrome at the cellular level. Addiction Biology, 9: 137-49.
6. Cotman, C.W., & Monaghan, D.T. (1988). Ann. Rev. Neurosci, 11: 61-80.
7. Ikonomidou, C., Bosch, F., Miksa, M., Bittigau, P., Vockler, J., Dikranian, K., …Olney, J.W. (1999). Blockade of NMDA receptors and apoptotic neurodegeneration in the developing brain. Science, 283: 70-74.
8. Prus, A. (2013). An Introduction to Drugs and the Neuroscience of Behavior (pp. 344-6). Stamford, CT: Cengage Learning.
9. Olney, J.W., Wozniak, D.F., Jevtovic-Todorovic, V., & Ikonomidou, C. (2001). Glutamate signaling and the Fetal Alcohol Syndrome. MRDD Research Reviews, 7: 267-75.
10. Rout, U.K. (2005). Alcohol, GABA receptors, and neurodeveloipmental disorders. International Review of Neurobiology, 71: 217-37.
11. Sullivan, L. (1997). Alcohol and Health: Seventh Special Report to the US Congress (pp. 74-73). Darby, PA: Diane Publishing Co.
12. Kumar, S., Porcu, P., Werner, D.F., Matthews, D.B., Diaz-Granados, J.L., Helfand, R.S., & Morrow, A.L. (2009). The role of GABAA receptors in the acute and chronic effects of ethanol: a decade of progress. Psychopharmacology (Berl), 205(4): 529-64.
13. Xu, W., Cormier, R., Covey, D.F., Isenberg, K.E., Zorumski, C.F., & Mennerick, S. Slow death of postnatal hippocampal neurons by GABAA receptor overactivation. The Journal of Neuroscience, 20(9): 3147-56.
14. Kluck, R.M., Bossy-Wetzel, E., Green, D.R., & Newmeyer D.D. (1997). The release of cytochrome c from mitochondria: a primary site for Bcl-2 regulation of apoptosis. Science, 275: 1132-6.
15. Green, D.R., & Reed, J.C. (1998). Mitochondria and apoptosis. Science, 281: 1309-12.
16. Young, C., Klocke, B.J., Tenkova, E., Choi, J., Labruyere, J., Qin, Y-Q, Holzman, D.M., Roth, K.A., & Olney, J.W. (2003). Ethanol-induced neuronal apoptosis in vivo requires BAX in the developing mouse brain. Cell Death Differ, 10: 1148-55.
17. Porter, A.G., & Janicke, R.U. (1999). Emerging roles of caspase-3 in apoptosis. Cell Death Differ, 6(2): 99-104.
18. Pruett, D., Waterman, E.H., & Caughey, A.B. (2013). Fetal alcohol exposure: Consequences, diagnosis, and treatment. Obstet Gynecol Surv., 68(1): 62-9.
19. Ernhart, C.B., Sokol, R.J., Martier, S., Moron, P., Nadler, D., Ager, J.W., & Wolf, A. (1987). Alcohol teratogenicity in the human: a detailed assessment of specificity, critical period, and threshold. Am J Obstet Gynecol, 156(1): 33-9.
20. Pierce, D.R., & West, J.R. (1986). Blood alcohol concentration: a critical factor for producing fetal alcohol effects. Alcohol, 3: 269-72.
21. Servais, L., Hourez, R., Bearzatto, B., Gall, D., Schiffmann, S.N. & Cheron, G. (2007). Purkinje cell dysfunction and alteration of long-term synaptic plasticity in fetal alcohol syndrome. PNAS, 104(23): 9858-63.
22. Belmeguenai, A., Botta, P., Weber, J.T., Carta, M., De Ruiter, M., De Zeeuw, C.I., Balenzuela, C.F., & Hansel, C. (2008). Alcohol impairs long-term depression at the cerebellar parallel fiber-Purkinje cell synapse. J Neurophysiol, 6: 3167-74.
23. Coesmans, M., Weber, J.T., De Zeeuw, C.I., Hansel, C. (2004). Bidirectional parallel fiber plasticity in the cerebellum under climbing fiber control. Neuron, 44: 691-700.
24. Ichise, T., Kano, M., Hashimoto, K., Yanagihara, D., Nakao, K., Shigemoto, R., Katsuki, M., & Aiba, A. (2000). mGluR1 in Cerebellar Purkinje cells essential for long-term depression, synapse, elimination, and motor coordination. Science, 288: 1832-5.
25. Yuan, Q., Qiu, D.L., Weber, J.T., Hansel, C., & Knopfel, T. (2007). Climbing fiber-triggered metabotropic slow potentials enhance dendritic calcium transients and simple spike firing in cerebellar Purkinje cells. Mol Cell Neurosci, 35: 596-603.
26. Conquet,F., Bashir, Z.I., Davies, C.H., Daniel, H., Ferraguti, F., Bordi, F.,…Condé, F. (1994). Motor deficit and impairment of synaptic plasticity in mice lacking mGluR1. Nature, 372(6503): 237-43.
27. Aiba, A., Kano, M., Chen, C., Stanton, M.E., Fox, G.D., Herrup, K., Zwingman, T.A., Tonegawa, S. (1994). Deficient cerebellar long-term depression and impaired motor learning in mGluR1 mutant mice. Cell, 79(2): 377-88.
28. Sillevis Smitt, P.A., Kinoshita, A., De Leeuw, B., Moll, W., Coesmans, M., Jaarsmas, D., …Shigemoto, R. (2000). Paraneoplastic cerebellar ataxia due to autoantibodies against a glutamate receptor. N Engl J Med, 342: 21-7.
29. Miyata, M., Finch, E.A., Khiroug, L., Hashimoto, K., Hayasaka, S., Oda, S.I.,…Kano, M. (2000). Local calcium release in dendritic spines required for long-term synaptic depression. Neuron, 28: 233-44.
30. De Zeeuw, C.I., Hansel, C., Bian, F., Koekkoek, S.K.E., van Alphen, A.M., Lunden, D.J., & Oberdick, J. (1998). Expression of a protein kinase C inhibitor in Purkinje cells blocks cerebellar LTD and adaptation of the vestibulo-ocular reflex. Neuron, 20: 495-508.
31. Aggleton, J.P., & Brown, M.W. (1999). Episodic memory, amnesia, and the hippocampal-anterior thalamic axis. Behav Brain Sci, 22: 425-89.
32. Berman, R.F., & Hannigan, J.H. (2000). Effects of prenatal alcohol exposure on the hippocampus: spatial behavior, electrophysiology and neuroanatomy. Hippocampus, 10: 94-110.
33. Puglia, M.P., & Valenzuela, C.F. (2010). Repeated third trimester-equivalent ethanol exposure inhibits long-term potentiation in the hippocampal CA1 region of neonatal rats. Alcohol, 44: 283-90.
34. Puglia, M.P., & Valenzuela, C.F. (2010). Ethanol acutely inhibits ionotropic glutamate receptor-mediated responses and long-term potentiation in the developing CA1 hippocampus. Alcohol. Clin. Exp. Res., 34: 594-606.
35. Toso, L., Poggi, S.H., Roberson, R., Woodard, J., Park, J., Abebe, D., & Spong, C.Y. (2006). Prevention of alcohol-induced learning deficits in fetal alcohol syndrome mediated through NMDA and GABA receptors. Am J Obstet Gynecol, 194: 681-6.
36. Yasuda, H., Barth, A.L., Stellwagen, D., & Malenka, R.C. (2003). A developmental switch in the signaling cascades for LTP induction. Nat. Neurosci, 6: 15-16.
37. Yao, L., Arolfo, M.P., Dohrman, D.P., Jiang, Z., Fan, P., …Fuchs, S. (2002). Betagamma dimers mediate synergy of dopamine D2 and adenosine A2 receptor-stimulated PKA signaling and regulate ethanol consumption. Cell, 109: 733-43.
38. Nayak, A., Zastrow, D.J., Lickteig, R., Zahniser, N.R., & Browning, M.D. (1998). Maintenance of late-phase LTP is accompanied by PKA-dependent increase in AMPA receptor synthesis. Nature, 394: 680-3.

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