Lynch et al. Cognition enhancement in normal subjects one input protects subsequently induced potentiation at a second 2003),and does not disturb already potentiated contacts as likely input to the same region from the effects of the inhibitor (Frey required for a high capacity memory system.A very large body of and Morris,1997;Shires et al.,2012).Given the small number experimental work has confirmed the tight connection between of synapses that generate EPSPs of conventional amplitudes,it LTP and diverse instances of memory (e.g.,Roman et al.,1987; is extremely likely that connections from the two inputs are,for Rioult-Pedotti et al.,2000;Whitlock et al.,2006).Moreover,LTP the most part,located on different dendritic segments.It follows is intimately related to the theta rhythm,an oscillation long asso- then that proteins from the first episode must have been synthe- ciated with learning (Buzsaki,2005;Vertes,2005;Snider et al., sized,or traveled,throughout much of the dendritic arborization, 2013);i.e.,five brief(30 ms)bursts of high frequency stimulation a point that is reinforced by evidence for tagging in the apical den- pulses(a pattern that mimics"theta bursting"during learning) drites after stimulation of basal afferents (Alarcon et al.,2006).It prove to be near optimal for inducing extremely stable LTP but will be noted that these findings align with the broad idea that only when separated by the period of the theta wave (Larson continual learning maintains relevant proteins at levels sufficient et al.,1986;Capocchi et al.,1992).The reasons for this have been for LTP-related plasticity,obviating the need for synthesis after identified (Figure 1). individual learning events. These observations suggest the possibility of enhancing learn- The above discussion concerns interpretative issues rather than ing with drugs that promote theta activity and correlated bursts the likelihood of achieving enhancement using the transcription/of high frequency discharges.Agents such as physostigmine, translation strategy.It may well be the case that increasing within- that facilitate central cholinergic transmission,promote the theta cell levels of proteins that support consolidation reduces the rhythm (Olpe et al.,1987;Hasselmo,2006)and are reported requirements for encoding persistent memories and/or increases to improve learning scores in certain experimental situations. their stability.Signaling from synapses to the nucleus or to local Notably,drugs of this type are among the few treatments protein synthesis machinery involves many steps and so is likely approved for Alzheimer's Disease (Clarke and Francis,2005; to be a variable and somewhat uncertain process.It would not Noetzli and Eap,2013).However,cholinergic systems perform be surprising,then,if the ongoing production of memory-related varied functions in brain,some of which are homeostatic in elements operates at a less than optimal rate even in high per- nature.This likely explains why drugs targeting cholinergic forming,normal subjects.In line with this,there are multiple mechanisms have not gained widespread acceptance as plausi- demonstrations that treatment with compounds that inhibit par- ble enhancers.Another approach based on theta activity involves ticular histone deacetylases,leading to increased transcription of the large hyperpolarizing potentials triggered within target neu- select gene families,can markedly enhance memory after single rons by the short train of theta bursts used to induce LTP.These training sessions (Stefanko et al.,2009;McQuown et al.,2011).after-hyperpolarizing potentials(AHPs),set in motion by cell dis- Also of interest are the numerous studies showing that selective charges,persist throughout the duration of the theta train and phosphodiesterase-4 inhibitors have potent enhancing effects on serve to counteract the depolarization needed to unblock the memory.Inhibitors of this class(e.g.,Rolipram),drive the protein voltage dependent,synaptic NMDA receptors.Influx of calcium kinase A-CREB transcription pathway implicated in learning through these receptors,followed by release of the cation from in a broad array of animals (including invertebrates),and so intracellular stores,triggers the chain of events leading to poten- is argued to be a very ancient,evolutionarily conserved mem- tiation (Figure 1).AHPs are mediated by a set of voltage-and ory substrate (Tully et al.,2003;Normann and Berger,2008).calcium-sensitive potassium channels,prominent among which Evidence that the same results obtain after extensive experience is the SK3 channel (Hosseini et al.,2001).The bee toxin apamin with similar problems in the recent past,and presumably a great blocks this channel with some selectivity and,as predicted,aug- deal of learning-driven transcription,would constitute support ments post-synaptic responses to theta burst trains;this results in for there being less than optimal production of proteins needed a striking increase in the magnitude of LTP (Kramar et al.,2004). for encoding under normal circumstances.This would certainly While a number of studies have found substantial improve- encourage the idea that enhanced protein synthesis is a viable ments in rodent learning with apamin treatment (Ikonen and route to augmented memory. Riekkinen,1999;Brennan et al.,2008;Vick et al.,2010),this is not a likely enhancer because of toxicology issues.But given SYNAPTIC PLASTICITY AND MEMORY ENHANCEMENT increasing interest in applications of channel blockers for diverse Most mechanism-based efforts directed at improving memory clinical problems,the apamin results suggest an intriguing mech- have focused on synaptic plasticity and in particular the long term anistic target for the development of enhancers.It is of note in this potentiation (LTP)effect.Researchers since the late 19th cen- regard that Brain Derived Neurotrophic Factor (BDNF),which tury have argued that the enormous capacity of memory is best appears to be released from terminals by theta bursts(Balkowiec explained by assuming that physical encoding of new information and Katz,2000;Chen et al.,2010b),also reduces AHPs at least occurs at small numbers of connections between neurons.The in rats (Kramar et al,2004).Elevating endogenous levels of discovery of LTP demonstrated that individual synapses in the this neurotrophin,which can be achieved by pharmacological cortical telencephalon do in fact possess the properties expected manipulations described later,thus provides another avenue for for a memory substrate (Bliss and Collingridge,1993;Lynch, enhancement. 1998,2004b;Morris,2003).The increase in transmission strength Identification of the initial triggers for LTP,as schematized in (magnitude of EPSCs)develops quickly,persists for a remark- Figure 1,pointed to NMDA receptor-mediated calcium influxes able period (weeks at least)(Staubli and Lynch,1987;Abraham, as a logical target for enhancement.The existence of multiple Frontiers in Systems Neuroscience www.frontiersin.org May 2014 Volume 8 Article 90 3Lynch et al. Cognition enhancement in normal subjects one input protects subsequently induced potentiation at a second input to the same region from the effects of the inhibitor (Frey and Morris, 1997; Shires et al., 2012). Given the small number of synapses that generate EPSPs of conventional amplitudes, it is extremely likely that connections from the two inputs are, for the most part, located on different dendritic segments. It follows then that proteins from the first episode must have been synthe￾sized, or traveled, throughout much of the dendritic arborization, a point that is reinforced by evidence for tagging in the apical den￾drites after stimulation of basal afferents (Alarcon et al., 2006). It will be noted that these findings align with the broad idea that continual learning maintains relevant proteins at levels sufficient for LTP-related plasticity, obviating the need for synthesis after individual learning events. The above discussion concerns interpretative issues rather than the likelihood of achieving enhancement using the transcription / translation strategy. It may well be the case that increasing within￾cell levels of proteins that support consolidation reduces the requirements for encoding persistent memories and/or increases their stability. Signaling from synapses to the nucleus or to local protein synthesis machinery involves many steps and so is likely to be a variable and somewhat uncertain process. It would not be surprising, then, if the ongoing production of memory-related elements operates at a less than optimal rate even in high per￾forming, normal subjects. In line with this, there are multiple demonstrations that treatment with compounds that inhibit par￾ticular histone deacetylases, leading to increased transcription of select gene families, can markedly enhance memory after single training sessions (Stefanko et al., 2009; McQuown et al., 2011). Also of interest are the numerous studies showing that selective phosphodiesterase-4 inhibitors have potent enhancing effects on memory. Inhibitors of this class (e.g., Rolipram), drive the protein kinase A—CREB transcription pathway implicated in learning in a broad array of animals (including invertebrates), and so is argued to be a very ancient, evolutionarily conserved mem￾ory substrate (Tully et al., 2003; Normann and Berger, 2008). Evidence that the same results obtain after extensive experience with similar problems in the recent past, and presumably a great deal of learning-driven transcription, would constitute support for there being less than optimal production of proteins needed for encoding under normal circumstances. This would certainly encourage the idea that enhanced protein synthesis is a viable route to augmented memory. SYNAPTIC PLASTICITY AND MEMORY ENHANCEMENT Most mechanism-based efforts directed at improving memory have focused on synaptic plasticity and in particular the long term potentiation (LTP) effect. Researchers since the late 19th cen￾tury have argued that the enormous capacity of memory is best explained by assuming that physical encoding of new information occurs at small numbers of connections between neurons. The discovery of LTP demonstrated that individual synapses in the cortical telencephalon do in fact possess the properties expected for a memory substrate (Bliss and Collingridge, 1993; Lynch, 1998, 2004b; Morris, 2003). The increase in transmission strength (magnitude of EPSCs) develops quickly, persists for a remark￾able period (weeks at least) (Staubli and Lynch, 1987; Abraham, 2003), and does not disturb already potentiated contacts as likely required for a high capacity memory system. A very large body of experimental work has confirmed the tight connection between LTP and diverse instances of memory (e.g., Roman et al., 1987; Rioult-Pedotti et al., 2000; Whitlock et al., 2006). Moreover, LTP is intimately related to the theta rhythm, an oscillation long asso￾ciated with learning (Buzsaki, 2005; Vertes, 2005; Snider et al., 2013); i.e., five brief (30 ms) bursts of high frequency stimulation pulses (a pattern that mimics “theta bursting” during learning) prove to be near optimal for inducing extremely stable LTP but only when separated by the period of the theta wave (Larson et al., 1986; Capocchi et al., 1992). The reasons for this have been identified (Figure 1). These observations suggest the possibility of enhancing learn￾ing with drugs that promote theta activity and correlated bursts of high frequency discharges. Agents such as physostigmine, that facilitate central cholinergic transmission, promote the theta rhythm (Olpe et al., 1987; Hasselmo, 2006) and are reported to improve learning scores in certain experimental situations. Notably, drugs of this type are among the few treatments approved for Alzheimer’s Disease (Clarke and Francis, 2005; Noetzli and Eap, 2013). However, cholinergic systems perform varied functions in brain, some of which are homeostatic in nature. This likely explains why drugs targeting cholinergic mechanisms have not gained widespread acceptance as plausi￾ble enhancers. Another approach based on theta activity involves the large hyperpolarizing potentials triggered within target neu￾rons by the short train of theta bursts used to induce LTP. These after-hyperpolarizing potentials (AHPs), set in motion by cell dis￾charges, persist throughout the duration of the theta train and serve to counteract the depolarization needed to unblock the voltage dependent, synaptic NMDA receptors. Influx of calcium through these receptors, followed by release of the cation from intracellular stores, triggers the chain of events leading to poten￾tiation (Figure 1). AHPs are mediated by a set of voltage- and calcium-sensitive potassium channels, prominent among which is the SK3 channel (Hosseini et al., 2001). The bee toxin apamin blocks this channel with some selectivity and, as predicted, aug￾ments post-synaptic responses to theta burst trains; this results in a striking increase in the magnitude of LTP (Kramar et al., 2004). While a number of studies have found substantial improve￾ments in rodent learning with apamin treatment (Ikonen and Riekkinen, 1999; Brennan et al., 2008; Vick et al., 2010), this is not a likely enhancer because of toxicology issues. But given increasing interest in applications of channel blockers for diverse clinical problems, the apamin results suggest an intriguing mech￾anistic target for the development of enhancers. It is of note in this regard that Brain Derived Neurotrophic Factor (BDNF), which appears to be released from terminals by theta bursts (Balkowiec and Katz, 2000; Chen et al., 2010b), also reduces AHPs at least in rats (Kramar et al., 2004). Elevating endogenous levels of this neurotrophin, which can be achieved by pharmacological manipulations described later, thus provides another avenue for enhancement. Identification of the initial triggers for LTP, as schematized in Figure 1, pointed to NMDA receptor-mediated calcium influxes as a logical target for enhancement. The existence of multiple Frontiers in Systems Neuroscience www.frontiersin.org May 2014 | Volume 8 | Article 90 | 3