Antagonism of lateral amygdala alpha1-adrenergic receptors facilitates fear conditioning and long-term potentiation

Norepinephrine receptors have been studied in emotion, memory, and attention. However, the role of alpha1-adrenergic receptors in fear conditioning, a major model of emotional learning, is poorly understood. We examined the effect of terazosin, an alpha1-adrenergic receptor antagonist, on cued fear conditioning. Systemic or intra-lateral amygdala terazosin delivered before conditioning enhanced short- and long-term memory. Terazosin delivered after conditioning did not affect consolidation. In vitro, terazosin impaired lateral amygdala inhibitory postsynaptic currents leading to facilitation of excitatory postsynaptic currents and long-term potentiation. Since alpha1 blockers are prescribed for hypertension and post-traumatic stress disorder, these results may have important clinical implications.Although norepinephrine (NE) has been widely studied as an important modulator of memory and emotion, comparatively little is known about the role of NE in amygdala-dependent Pavlovian fear conditioning, a major model for understanding the neural basis of fear learning and memory. In fear conditioning, an emotionally neutral conditioned stimulus (CS; i.e., tone) is temporally paired with an aversive unconditioned stimulus (US; i.e., footshock). After very few pairings, a lasting, robust CS–US association is acquired, and the CS elicits stereotypical defensive responses, including behavioral freezing (Blanchard and Blanchard 1969; Bolles and Fanselow 1980).The lateral nucleus of the amygdala (LA) is a key structure underlying fear conditioning (LeDoux 2000). Convergence of CS and US information in LA is believed to play an important role in initiating synaptic plasticity. Long-term potentiation (LTP)-like changes in LA CS processing are critical for fear memory storage (LeDoux 2000; Blair et al. 2001; Maren 2001; Walker and Davis 2002). LA receives auditory CS inputs from the thalamus and cortex and connects directly and indirectly with the central nucleus of the amygdala to control expression of Pavlovian fear responses.Of the noradrenergic receptor subtypes, alpha1 receptors have received the least attention in fear conditioning. LA receives NE-containing inputs from the locus coeruleus that fire tonically and phasically in response to aversive stimuli like footshock (Pitkänen 2000; Tanaka et al. 2000; Aston-Jones and Cohen 2005). Alpha1-adrenergic receptors are expressed in LA, most likely on both excitatory and inhibitory neurons (Jones et al. 1985; Domyancic and Morilak 1997). Alpha1 receptor activation stimulates GABA-mediated miniature inhibitory postsynaptic currents in LA (Braga et al. 2004), suggesting that alpha1 receptors contribute to inhibition in fear conditioning pathways. Several elegant experiments recently demonstrated that LA inhibition gates synaptic plasticity necessary for fear conditioning, and this inhibitory gate can be influenced by neuromodulators including NE (Stutzmann and LeDoux 1999; Shumyatsky et al. 2002; Bissière et al. 2003; Shaban et al. 2006; Shin et al. 2006; Tully et al. 2007). However, the role of alpha1 receptor activity in gating amygdala LTP and fear learning has never been examined.We hypothesized that alpha1 blockers would facilitate fear learning, possibly by impairing LA inhibition and facilitating LA LTP. To test this hypothesis, we injected rats with terazosin, a selective alpha1-adrenergic receptor antagonist, systemically or directly into LA before or after fear conditioning. We examined in vitro the effect of terazosin on LA pyramidal cell inhibitory postsynaptic currents (IPSCs) and excitatory postsynaptic currents (EPSCs) in response to fiber stimulation of the thalamic CS input pathway to LA, as well as the effect of terazosin on LA LTP in this same pathway. We found that intra-LA terazosin facilitated fear conditioning when injected before but not after training. We also found that terazosin impaired IPSCs in LA pyramidal cells, leading to facilitated EPSCs and LTP.Behavioral experiments were conducted on adult, male Sprague–Dawley rats (Hilltop Laboratory Animals) weighing approximately 300 g upon arrival. Rats were individually housed, maintained on a 12/12 h light/dark schedule, and allowed free access to food and water. Testing was conducted during the light phase. All procedures and experiments were approved by NYU''s Animal Care and Use Committee.For systemic injections, terazosin (20 mg/kg; Sigma) was dissolved in saline and injected intraperitoneally (i.p.) 30 min prior to conditioning in 1 mL/kg volume. For bilateral infusions, terazosin (125 ng/0.25 µL) was dissolved in aCSF and infused into the LA at 0.1 µL/min 30 min prior to or immediately after fear conditioning. Bilateral guide cannulae (22 gauge; Plastics One) aimed at LA (−3.3 mm anterior, 5.2 mm lateral, −7 mm dorsal to bregma) were surgically implanted as previously described (Sotres-Bayon et al. 2009). Rats were given at least 7 d to recover from surgery before testing. For infusions, dummy cannulae were removed, and infusion cannulae (28 gauge, +1 mm beyond guides) were inserted into guides. Infusion cannulae were connected to a 1.0 μL Hamilton syringe via polyethylene tubing. Infusion rate was controlled by a pump (PHD22/2000; Harvard Apparatus), and infusion cannulae were left in place for an additional 60 sec to allow diffusion of the solution away from the cannula tip, then dummy cannulae were replaced. Upon completion of the experiment, rats were euthanized, brains removed, and cannulae placements verified histologically as previously described (Sotres-Bayon et al. 2009).Two contexts (A and B) were used for all testing as previously described (Schiller et al. 2008). The grid floors in Context B were covered with black Plexiglas inserts to reduce generalization. No odors were used and chambers were cleaned between sessions. CSs were 30 sec, 5 kHz, 80 dB tones, and USs were 1 sec, 0.8 mA scrambled electric footshocks. Experiments consisted of two phases separated by 48 h: (1) fear conditioning in Context A and (2) long-term memory (LTM) test in Context B. On Day 1, rats were placed in Context A, allowed 5 min to acclimate, and then received three CS–US pairings separated by variable 5 min ITIs. On Day 3, rats were placed in Context B and allowed 5 min to acclimate before receiving one CS-alone presentation.The index of fear in behavioral experiments was “freezing,” the absence of all non-respiratory movement (Blanchard and Blanchard 1971; Fanselow 1980). Following testing, freezing was manually scored from DVDs by a scorer blind to group specification. Graphs represent group means ± SEM. Statistical analysis was conducted with GraphPad Prism.Whole-cell electrophysiological recordings were obtained from LA pyramidal cells using in vitro coronal slices from rats aged P21–P30 d as described in Cunha et al. (2010). Terazosin was bath-applied for 10 min to achieve stable responses before testing. The cells were voltage-clamped using an Axopatch 200B amplifier at −35 mV for recording EPSCs and IPSCs. Synaptic responses were evoked with sharpened tungsten bipolar stimulating electrodes. Internal capsule fibers containing thalamic afferents were stimulated for paired-pulse facilitation (PPF) (ISI = 50 msec; 0.1 Hz) using a photoelectric stimulus isolation unit with a constant current output. Cells were rejected if access resistance (8–26 MΩ) changed more than 15%. Signals were filtered at 2 kHz and digitized (Digidata 1440 A; Axon Instruments), and peak amplitude, 10%–90% rise time, and IPSC decay time constants were analyzed offline using pCLAMP10.2 software (Axon Instruments).Brain slices for LTP experiments were prepared from rats aged 3–5 wk as in Johnson et al. (2008) and maintained on an interface chamber at 31°C. Glass recording electrodes (filled with aCSF, 5 MΩ resistance) were guided to LA neurons. Bipolar stainless steel stimulating electrodes (75 kΩ) were positioned medial to LA in internal capsule fibers. Orthodromic synaptic potentials were evoked via an isolated current generator (Digitimer; 100 μsec pulses of 0.3–0.7 mA). Evoked field potentials were recorded with an Axoclamp 2B amplifier and Axon WCP software (Axon Instruments). Data were analyzed offline using WCP PeakFit (Axon Instruments). LTP was measured as a change in evoked field potential amplitude.Baseline responses were monitored at 0.05 Hz for 30 min with a stimulus intensity of 40%–50% of maximum fEPSP before LTP induction. Terazosin (10 µM) was superfused for 15 min, and then LTP was elicited by three tetanus trains (100 Hz × 1 sec, 3 min ITI) with the same intensity and pulse duration as the baseline stimuli. In one experiment, picrotoxin (PTX; 75 µM) was present in the perfusion solution to block fast GABAergic signaling.     

Behavioral stress impairs long-term potentiation in rodent hippocampus

A number of hormones secreted from the pituitary-adrenal system during stress affect learning and memory processes. The phenomenon of hippocampal long-term potentiation (LTP) is viewed by many as a putative mechanism of memory storage and has proved a most valuable model for study of neuronal plasticity at the cellular level. The present study was conducted to investigate the possibility that stressful events which occur prior (in vivo) to the preparation of brain slices may influence the electrophysiology of the in vitro hippocampal explant when tested for LTP. Adult male rats (Long-Evans male X Sprague-Dawley female) were pair-housed 1 week prior to testing. One animal in each pair was either placed in a restraining tube for 30 min and received no tail shocks (Restraint) or placed in a restraining tube and received tail shocks (1 microA, 1 s) every minute for 30 min (Restraint + Shock). The other animal in each pair was taken directly from the home cage and received no restraint or tail shock (Control). In vitro hippocampal slices were then prepared immediately from these animals according to standard methods. Our results demonstrate a marked impairment of LTP in hippocampal explants taken from rats exposed to stress. The significance of this result with respect to cellular mechanisms underlying the relationship between stress, cognition, and learning is discussed.     

Cholinergic modulation of hippocampal CA1 basal-dendritic long-term potentiation

Extensive research suggests that long-term potentiation (LTP) may serve as a cellular mechanism for memory and that alterations in synaptic plasticity may underlie the gross memory impairments observed in patients with Alzheimer's disease. Cholinergic facilitation of hippocampal LTP in the behaving rat is a useful model for the study of the effects of anticholinesterase or other drugs on synaptic plasticity. Field excitatory postsynaptic potentials were recorded from the hippocampal CA1 region following excitation of the basal dendrites in behaving male Long-Evans rats. LTP was induced by a high-frequency train (200 Hz for 0.5s duration) following injection of the acetylcholinesterase inhibitor eserine sulfate (0.5 mg/kg, i.p.), specific muscarinic M1 receptor antagonist pirenzepine (21.2 microg/microl, i.c.v.), or saline (i.p. or i.c.v.). Pirenzepine was found to block basal-dendritic LTP when LTP was induced during walking, but not when LTP was induced during immobility. Eserine facilitated LTP when induction occurred during either immobility or walking. The present study demonstrates that an anticholinesterase enhances LTP in CA1 of the behaving rat, and that facilitation of basal-dendritic LTP during walking is mediated by muscarinic M1 receptors.     

Synapse specificity of long-term potentiation breaks down with aging

Memory shows age-related decline. According to the current prevailing theoretical model, encoding of memories relies on modifications in the strength of the synapses connecting the different cells within a neuronal network. The selective increases in synaptic weight are thought to be biologically implemented by long-term potentiation (LTP). Here, we report that tetanic stimulation of afferent fibers in slices from 12-mo-old mice triggers an LTP not restricted to the activated synapses. This phenomenon, which can be anticipated to hinder memory encoding, is suppressed by blocking either L-type Ca(++) channels or Ca(++)-induced Ca(++) release, both well known to become disregulated with aging.     

Co-induction of long-term potentiation and long-term depression at a central synapse in the leech

Most studies of long-term potentiation (LTP) have focused on potentiation induced by the activation of postsynaptic NMDA receptors (NMDARs). However, it is now apparent that NMDAR-dependent signaling processes are not the only form of LTP operating in the brain [Malenka, R. C., & Bear, M. F. (2004). LTP and LTD: An embarrassment of riches. Neuron, 44, 5–21]. Previously, we have observed that LTP in leech central synapses made by the touch mechanosensory neurons onto the S interneuron was NMDAR-independent [Burrell, B. D., & Sahley, C. L. (2004). Multiple forms of long-term potentiation and long-term depression converge on a single interneuron in the leech CNS. Journal of Neuroscience, 24, 4011–4019]. Here we examine the cellular mechanisms mediating T-to-S (T → S) LTP and find that its induction requires activation of metabotropic glutamate receptors (mGluRs), voltage-dependent Ca²⁺ channels (VDCCs) and protein kinase C (PKC). Surprisingly, whenever LTP was pharmacologically inhibited, long-term depression (LTD) was observed at the tetanized synapse, indicating that LTP and LTD were activated at the same time in the same synaptic pathway. This co-induction of LTP and LTD likely plays an important role in activity-dependent regulation of synaptic transmission.     

Input-specific long-term potentiation in the rat lateral amygdala of horizontal slices

Long-term potentiation (LTP) at input synapses to the lateral nucleus of the amygdala (LA) is a candidate mechanism for memory storage during fear learning. Cellular mechanisms of LTP have been nearly exclusively investigated in coronal brain slices. In our experiments, we used a horizontal brain slice preparation of rats that preserved most of the connections to cortical areas and the hippocampus. The stimulation electrodes were located either within the external capsule (EC) or the LA. The aim of the present study was to investigate the mechanisms of LTP induced either by weak theta burst stimulation (TBS) or strong high frequency stimulation (HFS) using the two different stimulation sites. Whereas both TBS and HFS of afferences running through the LA induced stable LTP, TBS failed to induce LTP of EC-inputs to the LA. The present findings also show that LTP in the LA exhibits vulnerability at different time windows after induction. The time window was dependent on the kind of stimulated afferences. Later LTP becomes resistant to disruption by low frequency stimulation. We could show that both used inputs depended on NMDA receptors for LTP-induction. LTP induced by stimulation of fibers within the LA was not altered by nifedipine (10 microM). In contrast, EC-induced LTP was dependent on L-type voltage-gated calcium channels (VGCC). Finally, we found a higher magnitude of LTP in females using TBS, whereas HFS did not cause gender-specific differences. Our study supports the conclusion that the form of LA-LTP depend on which afferences are activated and what pattern of stimulation is used to induce LTP.     

SGK protein kinase facilitates the expression of long-term potentiation in hippocampal neurons

Previous studies showed that the serum- and glucocorticoid-inducible kinase (sgk) gene plays an important role in long-term memory formation. The present study further examined the role of SGK in long-term potentiation (LTP). The dominant-negative mutant of sgk, SGKS422A, was used to inactivate SGK. Results revealed a time-dependent increase in SGK phosphorylation after tetanization with a significant effect observed 3 h and 5 h later. Transfection of SGKS422A impaired the expression, but not the induction, of LTP. Furthermore, the constitutively active sgk, SGKS422D, up-regulated postsynaptic density-95 expression in the hippocampus. These results together support the role of SGK in neuronal plasticity.     

Hippocampal CA1 kindling but not long-term potentiation disrupts spatial memory performance

Long-term synaptic enhancement in the hippocampus has been suggested to cause deficits in spatial performance. Synaptic enhancement has been reported after hippocampal kindling that induced repeated electrographic seizures or afterdischarges (ADs) and after long-term potentiation (LTP) defined as synaptic enhancement without ADs. We studied whether repeated stimulations that gave LTP or ADs resulted in spatial performance deficits on the radial arm maze (RAM) and investigated the minimal number of ADs required for such deficits. Three experimental groups were run as follows: (1) 5 hippocampal ADs in 1 d (5-AD group), (2) 10 hippocampal ADs in 2 d (10-AD group), and (3) 12 -frequency primed-burst stimulations (PBSs) in 2 d in order to induce LTP without ADs (LTP group). Each experimental group was run together with a control group during the same time period. Rats were first trained in a spatial task on a radial arm maze with four of the eight arms baited, then given control or experimental treatment, and maze performance was tested in the first week (1-4 d) and fourth week (22-25 d) after treatment. Basal dendritic population excitatory postsynaptic potentials (pEPSPs) and medial perforant path (MPP)-evoked dentate gyrus population spike and polysynaptic CA1 excitation were recorded before and after experimental and control treatment. Spatial memory errors, in particular reference memory errors, were significantly higher in the 10-AD kindled group than any other group on the first and fourth week after treatment. Spatial memory errors were not significantly different in the 5-AD and LTP groups as compared with any control groups at any time. Basal dendritic pEPSP in CA1 was enhanced for about 1 wk after 12 PBSs, 10 ADs, or 5 ADs, while the dentate gyrus population spike and CA1 polysynaptic excitation evoked by MPP was increased for up to 4 wk after 10 ADs, but not 12 PBSs. Thus, distributed alteration of multiple synaptic transmission in the entorhinal-hippocampal circuit, but not LTP at the basal dendritic synapses in CA1, may disrupt spatial performance after 10 hippocampal ADs.     

Alpha3-integrins are required for hippocampal long-term potentiation and working memory

Integrins comprise a large family of heterodimeric, transmembrane cell adhesion receptors that mediate diverse neuronal functions in the developing and adult CNS. Recent pharmacological and genetic studies have suggested that beta1-integrins are critical in synaptic plasticity and memory formation. To further define the role of integrins in these processes, we generated a postnatal forebrain and excitatory neuron-specific knockout of alpha3-integrin, one of several binding partners for beta1 subunit. At hippocampal Schaffer collateral-CA1 synapses, deletion of alpha3-integrin resulted in impaired long-term potentiation (LTP). Basal synaptic transmission and paired-pulse facilitation were normal in the absence of alpha3-integrin. Behavioral studies demonstrated that the mutant mice were selectively defective in a hippocampus-dependent, nonmatch-to-place working memory task, but were normal in other hippocampus-dependent spatial tasks. The impairment in LTP and working memory is similar to that observed in beta1-integrin conditional knockout mice, suggesting that alpha3-integrin is the functional binding partner for beta1 for these processes in the forebrain.     

Hormonal and monoamine signaling during reinforcement of hippocampal long-term potentiation and memory retrieval

Recently it was shown that holeboard training can reinforce, i.e., transform early-LTP into late-LTP in the dentate gyrus during the initial formation of a long-term spatial reference memory in rats. The consolidation of LTP as well as of the reference memory was dependent on protein synthesis. We have now investigated the transmitter systems involved in this reinforcement and found that LTP-consolidation and memory retrieval were dependent on β-adrenergic, dopaminergic, and mineralocorticoid receptor (MR) activation, whereas glucocorticoid receptors (GRs) were not involved. Blockade of the β-adrenergic signaling pathway significantly increased the number of reference memory errors compared with MR and dopamine receptor inhibition. In addition, β-adrenergic blockade impaired the working memory. Therefore, we suggest that β-adrenergic receptor activation is the main signaling system required for the retrieval of spatial memory. In addition, other modulatory interactions such as dopaminergic as well as MR systems are involved. This result points to specific roles of different modulatory systems during the retrieval of specific components of spatial memory. The data provide evidence for similar integrative interactions between different signaling systems during cellular memory processes.     

Spatiotemporal dynamics of long-term potentiation in rat insular cortex revealed by optical imaging

Long-term potentiation (LTP) of the gustatory cortex (GC), a part of the insular cortex (IC) around the middle cerebral artery, is a key process of gustatory learning and memory, including conditioned taste aversion learning. The rostral (rGC) and caudal GC (cGC) process different tastes; the rGC responds to hedonic and the cGC responds to aversive tastes. However, plastic changes of spatial interaction of excitatory propagation between the rGC and cGC remain unknown. The present study aimed to elucidate spatiotemporal profiles of excitatory propagation, induced by electrical stimulation (five train pulses) of the rGC/cGC before and after LTP induction, using in vivo optical imaging with a voltage-sensitive dye. We demonstrated that tetanic stimulation of the cGC induced long-lasting expansion of the excitation responding to five train stimulation of the cGC, and an increase in amplitude of optical signals in the IC. Excitatory propagation after LTP induction spread preferentially toward the rostral IC: the length constant (λ) of excitation, obtained by fitting optical signals with a monoexponential curve, was increased to 121.9% in the rostral direction, whereas λ for the caudal, dorsal, and ventral directions were 48.9%, 44.2%, and 62.5%, respectively. LTP induction was prevented by pre-application of D-APV, an NMDA receptor antagonist, or atropine, a muscarinic receptor antagonist, to the cortical surface. In contrast, rGC stimulation induced only slight LTP without direction preference. Considering the different roles of the rGC and cGC in gustatory processing, these characteristic patterns of LTP in the GC may be involved in a mechanism underlying conversion of palatability.     

"Silent" metaplasticity of the late phase of long-term potentiation requires protein phosphatases

The late phase of long-term potentiation (L-LTP) is correlated with some types of long-term memory, but the mechanisms by which L-LTP is modulated by prior synaptic activity are undefined. Activation of protein phosphatases by low-frequency stimulation (LFS) given before induction of L-LTP may significantly modify L-LTP. Using cellular electrophysiological recording methods in mouse hippocampal slices, we show that LFS given before induction of L-LTP inhibited L-LTP in an activity-dependent manner without affecting either basal synaptic strength or the early phase of LTP (E-LTP). This anterograde inhibitory effect of LFS was persistent, required N-methyl-D-aspartate (NMDA) receptor activation, and was blocked by inhibitors of protein phosphatase 1 (PP1) and protein phosphatase 2A (PP2A). These data indicate that certain patterns of LFS can activate PP1 and/or PP2A, and that long-lasting activation of these phosphatases by prior LFS can suppress the subsequent expression of L-LTP without affecting E-LTP. Because this inhibition of L-LTP is caused by prior synaptic activity that, alone, produced no net effect on synaptic efficacy, we suggest that this is a “silent” form of metaplasticity that may influence long-term information storage by modulating the capacity of synapses to express L-LTP after repeated bouts of activity.     

Corticosterone time-dependently modulates beta-adrenergic effects on long-term potentiation in the hippocampal dentate gyrus

Previous experiments in the hippocampal CA1 area have shown that corticosterone can facilitate long-term potentiation (LTP) in a rapid non-genomic fashion, while the same hormone suppresses LTP that is induced several hours after hormone application. Here, we elaborated on this finding by examining whether corticosterone exerts opposite effects on LTP depending on the timing of hormone application in the dentate gyrus as well. Moreover, we tested rapid and delayed actions by corticosterone on β-adrenergic-dependent changes in LTP. Unlike the CA1 region, our in vitro field potential recordings show that rapid effects of corticosterone do not influence LTP induced by mild tetanization in the hippocampal dentate gyrus, unless GABA_A receptors are blocked. In contrast, the β-adrenergic agonist isoproterenol does initiate a slow-onset, limited amount of potentiation. When corticosterone was applied concurrently with isoproterenol, a further enhancement of synaptic strength was identified, especially during the early stage of potentiation. Yet, treatment with corticosterone several hours in advance of isoproterenol fully prevented any effect of isoproterenol on LTP. This emphasizes that corticosterone can regulate β-adrenergic modulation of synaptic plasticity in opposite directions, depending on the timing of hormone application.     

Conditioned taste aversion modifies persistently the subsequent induction of neocortical long-term potentiation in vivo

The ability of neurons to modify their synaptic strength in an activity-dependent manner has a crucial role in learning and memory processes. It has been proposed that homeostatic forms of plasticity might provide the global regulation necessary to maintain synaptic strength and plasticity within a functional dynamic range. Similarly, it is considered that the capacity of synapses to express plastic changes is itself subject to variation dependent on previous experience. In particular, training in several behavioral tasks modifies the possibility to induce long-term potentiation (LTP). Our previous studies in the insular cortex (IC) have shown that induction of LTP in the basolateral amygdaloid nucleus (Bla)-IC projection previous to conditioned taste aversion (CTA) training enhances the retention of this task. The aim of the present study was to analyze whether CTA training modifies the ability to induce subsequent LTP in the Bla-IC projection in vivo. Thus, CTA trained rats received high frequency stimulation in the Bla-IC projection in order to induce LTP 48, 72, 96 and 120 h after the aversion test. Our results show that CTA training prevents the subsequent induction of LTP in the Bla-IC projection, for at least 120 h after CTA training. We also showed that pharmacological inhibition of CTA consolidation with anisomycin (1 μl/side; 100 μg/μl) prevents the CTA effect on IC-LTP. These findings reveal that CTA training produces a persistent change in the ability to induce subsequent LTP in the Bla-IC projection in a protein-synthesis dependent manner, suggesting that changes in the ability to induce subsequent synaptic plasticity contribute to the formation and persistence of aversive memories.     

A biologically plausible model of associative memory which uses disinhibition rather than long-term potentiation

Mammalian memory is commonly "explained" in terms of long-term potentiation (LTP) of excitatory synapses. However, depotentiation of inhibitory pathways (disinhibition) is also a known phenomenon in the brain. Artificial neural networks which are offered as partial models of the cerebrum traditionally encode memory by the potentiation of excitatory "synapses" in a manner which is thought of as analogous to LTP. Analysis shows that such models have seriously limited storage capacities. The models also depend on mechanisms which do not appear to be biologically plausible. This paper demonstrates that these difficulties are avoided by encoding memory by means of disinhibition rather than LTP. The resulting models are simple and plausible, though unconventional.     

Enhanced proliferation of progenitor cells following long-term potentiation induction in the rat dentate gyrus

The dentate gyrus (DG) is among the few areas in the mammalian brain where production of new neurons continues in the adulthood. Although its functional significance is not completely understood, several lines of evidence suggest the role of DG neurogenesis in learning and memory. Considering that long-term potentiation (LTP) is a prime candidate for the process underlying hippocampal learning and memory, these results raise the possibility that LTP and neurogenesis are closely related. Here, we investigated whether or not LTP induction in the afferent pathway triggers enhanced proliferation of progenitor cells in the DG. LTP was induced by tetanic stimulation in perforant path-DG synapses in one hemisphere, and the number of newly generated progenitor (BrdU-labeled) cells in the DG was quantified. Compared with the control hemisphere (stimulated with low-frequency pulses), the LTP-induced hemisphere contained a significantly higher number of newly generated progenitor cells in the dorsal as well as ventral DG. When CPP, an NMDA receptor antagonist, was administered, tetanic stimulation neither induced LTP nor enhanced progenitor cell proliferation, indicating that NMDA receptor activation, rather than tetanic stimulation per se, is responsible for enhanced progenitor proliferation in the control animal. Our results show that tetanic stimulation of perforant path sufficient to induce LTP increases progenitor proliferation in adult DG in an NMDA receptor-dependent manner.