UC Irvine UC Irvine Previously Published Works Title AMPA Receptor Modulation for Enhancing Plasticity and Treating Neuropathology Permalink https://escholarship.org/uc/item/4dj3w2pw Journal Mediographia, 36(3) ISSN 0243-3397 Authors Gall, CM Lynch, G Publication Date 2014 License https://creativecommons.org/licenses/by/4.0/ 4.0 Peer reviewed eScholarship.org Powered by the California Digital Library University of California Servie r: Looking to the future Neuroscience Innovation-driven partnerships IMPROVING COGNITION AND NEUROPLASTICITY AMPA receptor modulation for enhancing plasticity and treating neuropathology G. Lynch, C. M. Gall , USA Page 372 N EUROSCIENCE Improving cognition and neuroplasticity Peripheral injection of an ampakine allowed monkeys to perform well beyond the level that could be achieved with weeks of ‘tra‘ ining. Subsequent brain imaging AMPA receptor modulation studies showed that the drug pro - duced a striking network effect: the monkeys engaged additional cor - for enhancing plasticity and tical areas while dealing with mul - tiple, complex cues. These studies provide direct evidence that the treating neuropathology network extension effect obtained in physiology experiments occurs in living animals and results in ca - pacities beyond normal.” by G. Lynch and C. M. Gall, USA ositive allosteric modulators of Ͱ-amino-3-hydroxyl-5-methyl-4-isoxa - P zole-propionate (AMPA)–type glutamate receptors (“ampakines” and functionally related compounds) constitute a relatively new class of psy - choactive drugs that enhance fast, excitatory transmission in the brain. Be - cause of this effect, ampakines reduce the threshold for inducing memory- related changes to synapses and improve learning in animals across species and paradigms. While most CNS drugs target neurons that project in a one- step, parallel fashion to a multitude of sites, ampakine-type agents act on the multiple connections found in serial brain networks. This results in a multipli - er effect for the drug, likely to be most pronounced in the elaborate circuits ▲ found in the cortex, thereby intensifying cortical regulation of lower brain Gary LYNCH, PhD Department of Psychiatry and areas (“pharmacological encephalization”). Evidence that the compounds are Human Behavior, Department effective in animal models of psychiatric disorders associated with abnormal of Anatomy and Neurobiology brainstem activity is in agreement with this hypothesis. The possibility that University of California Irvine, California, USA expanding cortical networks will lead to cognitive, as opposed to memory, en - Christine M. GALL, PhD hancement in normal brains is largely unexplored. Finally, positive modulators Department of Anatomy and increase the production of brain growth factors that promote plasticity and Neurobiology, Department of neuronal viability; upregulation is associated with neuroprotection, growth, Neurobiology and Behavior University of California and improved functional outcomes in different disease models. Irvine, California, USA Medicographia. 2014;36:372-382 (see French abstract on page 382) wenty years have passed since the introduction of peripherally administered T compounds that positively modulate a-amino-3-hydroxyl-5-methyl-4-isoxa - zole-propionate (AMPA)–type glutamate receptors (ie, ampakines) and thereby rapidly enhance fast, excitatory transmissions in the brain. 1 The motivation for devel - oping such drugs was relatively straightforward: increasing the size of postsynap - tic responses should facilitate the opening of voltage sensitive N-methyl-D-aspar - tic acid (NMDA) receptors colocalized with AMPA receptors. Given that NMDA recep tors trigger the learning-related long-term potentiation (LTP) effect, ampakines were expected to potently facilitate memory encoding. 2 These predictions have been con firmed by several groups. However, it quickly became evident that the drugs Address for correspondence: might have broader uses due to two effects, one obvious and the other not, that Professor Gary Lynch, follow from augmented transmission at excitatory contacts. First, glutamatergic 837 Health Science Road, Room 1126, University of California, Irvine, synapses mediate communication within the myriad networks used by the cortical te - CA 92697-1275, USA lencephalon to regulate lower brain regions and to execute the dense computa - (e-mail: [email protected]) tions underlying cognition. Positive modulators therefore have potential therapeu - www.medicographia.com tic applications in psychiatric disorders involving brainstem biogenic amine 372 MEDICOGRAPHIA , Vol 36, No . 3, 2014 AMPA receptor modulators: promises and problems – Lynch and Gall N EUROSCIENCE Improving cognition and neuroplasticity systems 3 and, more spec ulatively, for enhancing cognition. high frequency transmitter release. 13 While it was commonly Second, greater than normal excitatory postsynaptic currents thought that desensitization terminates synaptic EPSCs, the (EPSCs) will increase the like lihood of cell discharges, an ef - decay phase of AMPA receptor–mediated synaptic currents fect known to upregulate tran scription of brain-derived neu - appears to be governed by the rate of deactivation. 14 Notably, rotrophic factor (BDNF). 4 Such an effect raised the possibil - the rate constants for deactivation and desensitization are not ity of using ampakine-type drugs to treat brain damage. greatly dissimilar, and routinely used experimental methods (eg, whole cell recording) can shift the balance between them These ideas received considerable preclinical support and, as in favor of the latter. 15 This is a point of some significance for might be expected, the positive modulator strategy evolved the design of modulator experiments. significantly over the subsequent two decades. This is an ap - propriate point to survey the status of the field and to con - The binding pocket for ampakines was identified by x-ray crys - sider possible future directions. This review begins with a brief tallography of the receptor-drug complex. The pertinent site is description of the mode of action for ampakine-like drugs and found at the hinge of the extracellular V near the dimer inter - then turns to specific applications. The issue of why, given face, 16 a position that: (i) controls the kinetics for reopening their substantial success in animal studies, the compounds of the V and transmitter release (deactivation); and (ii) main - have not progressed further in clinical development will also tains dimerization, thus preventing the receptor from becom - be discussed. ing desensitized. These crystallography findings accord with physiological results showing that ampakines can slow in both Mode of action deactivation and desensitization. 13 However, the relative effect The first, centrally active, positive AMPA receptor modulators on the two processes is variant-dependent; some modulators were small benzamide structures (≈300 Da) 5 that, with further act predominantly on deactivation, others on desensitization, development, resulted in two large subtypes. Later studies by and still others on both. The first group increases the ampli - other investigators, primarily at Servier, Eli Lilly, and Glaxo, gen - tude of synaptic responses while having minor effects on their erated pyridothiadiazine, 6 biarylpropylsulfonamide, 7 and 5’- duration (referred to as type A ampakines), while the second alkyl-benzothiadiazide 8 families that similarly enhance AMPA group (type B) causes a significant prolongation of the exci - receptor currents. 9 Compounds from each of these groups tatory postsynaptic potential (EPSP) (Figure 1, page 374). 17 proved effective in various animal tests. As will be described, these two categories have substantial - ly different functional effects. AMPA receptors are tetramers composed of several possi - ble combinations of four homologous subunits (GluA1, GluA2, Enhancement of memory and cognition GluA3, and GluA4) each with RNA splicing variants (“flip” and u Synaptic plasticity and memory “flop”). 10 X-ray crystallography 11 and site-directed mutagene - Brain waves during learning in mammals, including humans, sis 12 work found that extracellular domains for individual GluA contain high levels of 4-8 Hz q activity; recordings from indi - subunits create a V structure that contains the glutamate bind - vidual neurons routinely detect multiple discharges (bursts) ing pocket. Notably, adjacent subunits form dimers (ie, two during the peaks of the rhythm. Remarkably, activation of in - dimers per one tetrameric receptor). Ligand binding causes puts to the cells in a pattern that mimics q bursts causes a the extracellular V domains to converge and thereby trap the marked and extremely persistent increase in the amplitude of ligand; this generates tension on the transmembrane segment EPSCs elicited by subsequent single stimulation pulses. 18,19 of the receptor and a shift to the channel open state. The V This long-term potentiation (LTP) effect is broadly accepted to then reopens, releases the transmitter, and terminates ion flux, be the substrate for many types of memory. If so, then there events referred to as “deactivation”. However, binding can dis - is a good possibility that enhancing LTP will produce corre - rupt dimerization, leaving the V structures and the channel sponding effects on long-term memory. As mentioned, pos - closed. This paradoxical (bound, but closed receptor) state is itive modulation of AMPA receptors potently facilitates the likely responsible