Spatiotemporal expression of PSD‐95 in Fmr1 knockout mice brain

To investigate and compare the spatial and temporal expression of post‐synaptic density‐95 (PSD‐95) in Fmr1 knockout mice (the animal model of fragile X syndrome, FXS) and wild‐type mice brain, on postnatal day 7 (P7), P14, P21, P28 and P90, mice from each group were decapitated, and three principal brain regions (cerebral cortex, hippocampus and cerebellum) were obtained and stored for later experiments. PSD‐95 mRNA in the three brain areas was analyzed with quantitative RT‐PCR. PSD‐95 protein was measured by immunohistochemical staining and Western blot. In the three principal brain areas of Fmr1 knockout mice and wild‐type mice, the expression of PSD‐95 mRNA and protein were detected at the lowest levels on P7, and then significantly increased on P14, reaching the peak levels in adolescents or adults. Moreover, it was found that PSD‐95 mRNA and protein in the hippocampus were significantly decreased in Fmr1 knockout mice during the developmental period (P7, P14, P21 and P28) as well as at adulthood (P90) (P < 0.05, and P < 0.01, respectively). However, there was no significant difference of expression of PSD‐95 in the cortex and cerebellum between Fmr1 knockout and wild mice. The expression of PSD‐95 in the hippocampus might be regulated by fragile X mental retardation protein (FMRP) during mice early developmental and adult periods. It is suggested that impairment of PSD‐95 is possibly involved in hippocampal‐dependent learning defects, which are common in people with FXS.     

PKMζ is necessary and sufficient for synaptic clustering of PSD‐95

The persistent activity of protein kinase Mzeta (PKMζ), a brain‐specific, constitutively active protein kinase C isoform, maintains synaptic long‐term potentiation (LTP). Structural remodeling of the postsynaptic density is believed to contribute to the expression of LTP. We therefore examined the role of PKMζ in reconfiguring PSD‐95, the major postsynaptic scaffolding protein at excitatory synapses. In primary cultures of hippocampal neurons, PKMζ activity was critical for increasing the size of PSD‐95 clusters during chemical LTP (cLTP). Increasing PKMζ activity by overexpressing the kinase in hippocampal neurons was sufficient to increase PSD‐95 cluster size, spine size, and postsynaptic AMPAR subunit GluA2. Overexpression of an inactive mutant of PKMζ did not increase PSD‐95 clustering, and applications of the ζ‐pseudosubstrate inhibitor ZIP reversed the PKMζ‐mediated increases in PSD‐95 clustering, indicating that the activity of PKMζ is necessary to induce and maintain the increased size of PSD‐95 clusters. Thus the persistent activity of PKMζ is both necessary and sufficient for maintaining increases of PSD‐95 clusters, providing a unified mechanism for long‐term functional and structural modifications of synapses. © 2011 Wiley Periodicals, Inc.     

Enhanced spatial memory and hippocampal long‐term potentiation in p75 neurotrophin receptor knockout mice

Previous reports have described increases in the size and number of cholinergic neurons in the basal forebrain in p75 neurotrophin receptor (p75^NTR) knockout mice. In an earlier study, we also found improved spatial memory in these mice, raising the possibility that p75^NTR regulates hippocampal function by its effects on the cholinergic basal forebrain. We therefore investigated hippocampal long‐term potentiation in p75^NTR knockout mice that shared the same genetic background as control 129/Sv mice. We also investigated heterozygous mice, carrying just one functional p75^NTR allele. The p75^NTR knockout mice had enhanced long‐term potentiation in the Schafer collateral fiber synapses of the hippocampus. Heterozygous mice had an intermediate level, greater than controls but less than knockout mice. Hippocampal choline acetyltransferase activity was also markedly elevated in p75^NTR knockout mice, with a smaller increase in heterozygous mice. In the Barnes maze, p75^NTR knockout mice displayed markedly superior learning to controls, and this was evident over the three age brackets tested. At each age, the performance of heterozygous mice was intermediate to the other groups. In the open field test, p75^NTR knockout mice exhibited greater stress‐related behavioral responses, including freezing, than did control animals. There were no differences between the three groups in a test of olfactory function. The dose‐dependent effects of p75^NTR gene copy number on hippocampal plasticity and spatial memory indicate that p75^NTR has profound effects on hippocampal function. Bearing in mind that p75^NTR is very sparsely expressed in the adult hippocampus and has a potent effect on hippocampal choline acetyltransferase activity, the effects of p75^NTR on hippocampal function are likely to be mediated indirectly, by its actions on basal forebrain cholinergic neurons. © 2009 Wiley‐Liss, Inc.     

Expression of the postsynaptic scaffold PSD‐95 and development of synaptic physiology during giant terminal formation in the auditory brainstem of the chicken

In the avian nucleus magnocellularis (NM) endbulb of Held giant synapses develop from temporary bouton terminals. The molecular regulation of this process is not well understood. Furthermore, it is unknown how the postsynaptic specialization of the endbulb synapses develops. We therefore analysed expression of the postsynaptic scaffold protein PSD‐95 during the transition from bouton‐to‐endbulb synapses. PSD‐95 has been implicated in the regulation of the strength of glutamatergic synapses and could accordingly be of functional relevance for giant synapse formation. PSD‐95 protein was expressed at synaptic sites in embryonic chicken auditory brainstem and upregulated between embryonic days (E)12 and E16. We applied immunofluorescence staining and confocal microscopy to quantify pre‐and postsynaptic protein signals during bouton‐to‐endbulb transition. Giant terminal formation progressed along the tonotopic axis in NM, but was absent in low‐frequency NM. We found a tonotopic gradient of postsynaptic PSD‐95 signals in NM. Furthermore, PSD‐95 immunosignals showed the greatest increase between E12 and E15, temporally preceding the bouton‐to‐endbulb transition. We then applied whole‐cell electrophysiology to measure synaptic currents elicited by synaptic terminals during bouton‐to‐endbulb transition. With progressing endbulb formation postsynaptic currents rose more rapidly and synapses were less susceptible to short‐term depression, but currents were not different in amplitude or decay‐time constant. We conclude that development of presynaptic specializations follows postsynaptic development and speculate that the early PSD‐95 increase could play a functional role in endbulb formation.     

Changes in hippocampal synaptic functions and protein expression in monosodium glutamate‐treated obese mice during development of glucose intolerance

Glucose is the sole neural fuel for the brain and is essential for cognitive function. Abnormalities in glucose tolerance may be associated with impairments in cognitive function. Experimental obese model mice can be generated by an intraperitoneal injection of monosodium glutamate (MSG; 2 mg/g) once a day for 5 days from 1 day after birth. MSG‐treated mice have been shown to develop glucose intolerance and exhibit chronic neuroendocrine dysfunction associated with marked cognitive malfunctions at 28–29  weeks old. Although hippocampal synaptic plasticity is impaired in MSG‐treated mice, changes in synaptic transmission remain unknown. Here, we investigated whether glucose intolerance influenced cognitive function, synaptic properties and protein expression in the hippocampus. We demonstrated that MSG‐treated mice developed glucose intolerance due to an impairment in the effectiveness of insulin actions, and showed cognitive impairments in the Y‐maze test. Moreover, long‐term potentiation (LTP) at Schaffer collateral–CA1 pyramidal synapses in hippocampal slices was impaired, and the relationship between the slope of extracellular field excitatory postsynaptic potential and stimulus intensity of synaptic transmission was weaker in MSG‐treated mice. The protein levels of vesicular glutamate transporter 1 and GluA1 glutamate receptor subunits decreased in the CA1 region of MSG‐treated mice. These results suggest that deficits in glutamatergic presynapses as well as postsynapses lead to impaired synaptic plasticity in MSG‐treated mice during the development of glucose intolerance, though it remains unknown whether impaired LTP is due to altered inhibitory transmission. It may be important to examine changes in glucose tolerance in order to prevent cognitive malfunctions associated with diabetes.     

Age‐related synaptic dysfunction in Tg2576 mice starts as a failure in early long‐term potentiation which develops into a full abolishment of late long‐term potentiation

Tg2576 mice are widely used to study amyloid‐dependent synaptic dysfunction related to Alzheimer's disease. However, conflicting data have been reported for these mice with regard to basal transmission as well as the in vitro correlate of memory, long‐term potentiation (LTP). Some studies show clear impairments, whereas others report no deficiency. The present study uses hippocampal slices from 3‐, 10‐, and 15‐month‐old wild‐type (WT) and Tg2576 mice to evaluate synaptic function in each group, including experiments to investigate basal synaptic transmission, short‐ and long‐term plasticity by inducing paired‐pulse facilitation, and both early and late LTP. We show that synaptic function remains intact in hippocampal slices from Tg2576 mice at 3 months of age. However, both early and late LTP decline progressively during aging in these mice. This deterioration of synaptic plasticity starts affecting early LTP, ultimately leading to the abolishment of both forms of LTP in 15‐month‐old animals. In comparison, WT littermates display normal synaptic parameters during aging. Additional pharmacological investigation into the involvement of NMDA receptors and L‐type voltage‐gated calcium channels in LTP suggests a distinct mechanism of induction among age groups, demonstrating that both early and late LTP are differentially affected by these channels in Tg2576 mice during aging. © 2015 Wiley Periodicals, Inc.     

Neuroprotective effect of amantadine on corticosterone‐induced abnormal glutamatergic synaptic transmission of CA3‐CA1 pathway in rat's hippocampal slices

Depression is a psychiatric disorder and chronic stress, leading to altered glucocorticoid secretion patterns, is one of the factors that induce depression. Our previous study showed that amantadine significantly attenuated the impairments of synaptic plasticity and cognitive function a rat model of CUS. However, little is known regarding the underlying mechanism. In the present study, the whole‐cell patch‐clamp technique was applied to examine the protection effect of amantadine on the hippocampus CA3‐CA1 pathway. Evoked excitatory postsynaptic currents (eEPSCs), miniature excitatory postsynaptic currents (mEPSCs), paired‐pulse ratio (PPR) and the action potentials of CA3 neurons were recorded. Our data showed that corticosterone increased the amplitude of eEPSCs and decreased the value of paired‐pulse ratio (PPR), but both of them were significantly reversed by amantadine. In addition, the frequency of mEPSC was considerably increased by corticosterone, but it was reduced by amantadine. Moreover, we used the Fluo‐3/AM image to detect the Ca²⁺ influx in primary cultured hippocampal neurons. The results showed that the intracellular calcium levels were significantly decreased by amantadine in the corticosterone treated neurons. Additionally, the superoxide dismutase (SOD) and catalase (CAT) activities were reduced by corticosterone, while they were enhanced by either amantadine or low‐calcium artificial cerebral spinal fluid (ACSF). These results suggest that amantadine significantly improves corticosterone‐induced abnormal glutamatergic synaptic transmission of CA3‐CA1 synapses presynaptically and alleviates the activities of antioxidant enzymes via regulating the calcium influx.     

Genetic deletion of melanin‐concentrating hormone neurons impairs hippocampal short‐term synaptic plasticity and hippocampal‐dependent forms of short‐term memory

The cognitive role of melanin‐concentrating hormone (MCH) neurons, a neuronal population located in the mammalian postero‐lateral hypothalamus sending projections to all cortical areas, remains poorly understood. Mainly activated during paradoxical sleep (PS), MCH neurons have been implicated in sleep regulation. The genetic deletion of the only known MCH receptor in rodent leads to an impairment of hippocampal dependent forms of memory and to an alteration of hippocampal long‐term synaptic plasticity. By using MCH/ataxin3 mice, a genetic model characterized by a selective deletion of MCH neurons in the adult, we investigated the role of MCH neurons in hippocampal synaptic plasticity and hippocampal‐dependent forms of memory. MCH/ataxin3 mice exhibited a deficit in the early part of both long‐term potentiation and depression in the CA1 area of the hippocampus. Post‐tetanic potentiation (PTP) was diminished while synaptic depression induced by repetitive stimulation was enhanced suggesting an alteration of pre‐synaptic forms of short‐term plasticity in these mice. Behaviorally, MCH/ataxin3 mice spent more time and showed a higher level of hesitation as compared to their controls in performing a short‐term memory T‐maze task, displayed retardation in acquiring a reference memory task in a Morris water maze, and showed a habituation deficit in an open field task. Deletion of MCH neurons could thus alter spatial short‐term memory by impairing short‐term plasticity in the hippocampus. Altogether, these findings could provide a cellular mechanism by which PS may facilitate memory encoding. Via MCH neuron activation, PS could prepare the day's learning by increasing and modulating short‐term synaptic plasticity in the hippocampus. © 2015 Wiley Periodicals, Inc.     

Distribution and analysis of hippocampal theta‐related cells in the pontine region of the urethane‐anesthetized rat

In the present study 99 cells were recorded in the pontine region of urethane‐anesthetized rats during: (1) the spontaneous occurrence of hippocampal formation (HPC) theta field activity; (2) sensory‐induced (tail pinch) theta field activity; and (3) large amplitude irregular field activity (LIA). Using the criteria of Colom and Bland (Brain Res 1997;422:277–286) for the classification of theta‐related cells, 58/99 cells (59%) were involved with changes in activity related to the occurrence of HPC theta field activity, 24/99 (24%) were non‐related, and 17/99 (17%) were related to the sensory input (tail pinch). All cells recorded discharged in a tonic, non‐rhythmic pattern in relation to the HPC field activity occurring during the three conditions. Of the 58 theta‐related cells, 52 (90%) were classified as tonic theta‐ON cells and 6 (10%) as tonic theta‐OFF cells. There were no clear regional differences in the distribution of cell types. Statistical analysis of the discharge rates of tonic theta‐ON cells during spontaneously occurring theta and tail pinch‐induced theta (tested on 48 cells) revealed that 22/48 (46 %) of these cells discharged at significantly higher rates during the faster theta field frequencies associated with tail pinches while 26/48 (54%) tonic theta‐ON cells did not change discharge rate between the spontaneously occurring theta and the tail pinch‐induced theta states. In addition, the discharges of 11/52 (21%) tonic theta‐ON cells exhibited weak to moderate correlations with the negative peak of HPC theta field activity recorded from the stratum moleculare of the dentate gyrus. Of the 17 cells related to the sensory stimulation (tail pinch), 12 (71%) cells increased discharge rate during the tail pinch and were classified as sensory activated, while 5 (29%) cells decreased discharge rate during the tail pinch and were classified as sensory inactivated. The results supported the following conclusions: (1) the main cells in the pontine region involved with changes in activity related to the occurrence of HPC theta field acitivity are tonic theta‐ON cells and tonic theta‐OFF cells; (2) a subpopulation of tonic theta‐ON cells coded the increasing intensity of activation of the ascending brainstem HPC synchronizing pathways by an increase in discharge rate; and (3) a smaller population of cells in the rostral pontine region appeared to be related to sensory stimulation, independent of theta‐related activity. Hippocampus 1999;9:288–302. © 1999 Wiley‐Liss, Inc.     

Transient appearance of Ca2+‐permeable AMPA receptors is crucial for the production of repetitive LTP‐induced synaptic enhancement (RISE) in cultured hippocampal slices

We have previously shown that repetitive induction of long‐term potentiation (LTP) by glutamate (100 μM, 3 min, three times at 24‐hr intervals) provoked long‐lasting synaptic enhancement accompanied by synaptogenesis in rat hippocampal slice cultures, a phenomenon termed RISE (repetitive LTP‐induced synaptic enhancement). Here, we examined the role of Ca²⁺‐permeable (CP) AMPA receptors (AMPARs) in the establishment of RISE. We first found a component sensitive to the Joro‐spider toxin (JSTX), a blocker of CP‐AMPARs, in a field EPSP recorded from CA3‐CA1 synapses at 2–3 days after stimulation, but this component was not found for 9–10 days. We also observed that rectification of AMPAR‐mediated current appeared only 2–3 days after stimulation, using a whole‐cell patch clamp recording from CA1 pyramidal neurons. These findings indicate that CP‐AMPAR is transiently expressed in the developing phase of RISE. The blockade of CP‐AMPARs by JSTX for 24 hr at this developing phase inhibited RISE establishment, accompanied by the loss of small synapses at the ultrastructural level. These results suggest that transiently induced CP‐AMPARs play a critical role in synaptogenesis in the developing phase of long‐lasting hippocampal synaptic plasticity, RISE.     

Osthole or imperatorin‐mediated facilitation of glutamate release is associated with a synaptic vesicle mobilization in rat hippocampal glutamatergic nerve endings

Osthole and imperatorin, two active compounds of Cnidium monnieri (L.) Cusson, have previously been shown to facilitate depolarization‐evoked glutamate release from rat hippocampal nerve terminals by increasing voltage‐dependent Ca²⁺ entry. In this study, we further investigated whether osthole and imperatorin possess an action at the exocytotic machinery itself, downstream of a Ca²⁺ influx. Our data showed that ionomycin‐induced glutamate release and KCl‐evoked FM1‐43 release were facilitated by osthole and imperatorin, suggesting that some steps after Ca²⁺ entry are regulated by these two compounds. Consistent with this, osthole or imperatorin‐mediated facilitation of ionomycin‐induced glutamate release was occluded by cytochalasin D that inhibits actin polymerization, implying that the disassembly of cytoskeleton is involved. In addition, the facilitatory action of osthole or imperatorin on ionomycin‐induced glutamate release was attenuated by the Ca²⁺/calmodulin‐dependent kinase II (CaMKII) inhibitor KN62. Furthermore, Western blotting analysis further showed that osthole or imperatorin significantly increased ionomycin‐induced phosphorylation of CaMKII and synapsin I, the main presynaptic target of CaMKII. These results suggest, therefore, that osthole or imperatorin‐mediated facilitation of glutamate release involves modulation of downstream events controlling synaptic vesicle recruitment and exocytosis, possibly through an increase of CaMKII activation and synapsin I phosphorylation, thereby increasing synaptic vesicle availability for exocytosis. Synapse 64:390–396, 2010. © 2009 Wiley‐Liss, Inc.     

Effect of myristoylated alanine-rich C kinase substrate (MARCKS) overexpression on hippocampus-dependent learning and hippocampal synaptic plasticity in MARCKS transgenic mice

The myristoylated alanine-rich C kinase substrate (MARCKS) is a primary substrate of protein kinase C (PKC) thought to regulate membrane-filamentous actin cytoskeletal plasticity in response to PKC activity in the regulation of synaptic efficacy. We have recently reported that MARCKS expression is significantly elevated (45%) in the hippocampus of DBA/2J mice, which exhibit impaired hippocampus-dependent learning and hippocampal long-term potentiation (LTP), compared with C57BL/6J mice. The latter finding led us to hypothesize that elevations in MARCKS expression are detrimental to hippocampal plasticity and function. To assess this more directly, we examined hippocampal (CA1) paired-pulse facilitation and LTP, and hippocampus-dependent learning in mice overexpressing MARCKS through the expression of a human MARCKS transgene (Tg+). The human MARCKS protein was confirmed to be expressed in the hippocampus of Tg+ mice but not in Tg- mice. Schaffer collateral paired-pulse facilitation, input-output responses, and LTP did not differ between Tg+ and Tg- mice, indicating that neurotransmitter release, short-term, and long-term synaptic plasticity are not impaired by MARCKS overexpression. In the Morris water maze, Tg+ mice exhibited a mild but significant spatial learning impairment during initial acquisition, and a more severe impairment during reversal training. Tg+ did not exhibit impaired swim speed or visible platform performance relative to Tg- mice, indicating the absence of gross sensorimotor deficits. Fear conditioning to either context or cue was not impaired in Tg+ mice. Behavioral deficits could not be attributed to differences in hippocampal PKC isozyme (alpha beta(II), gamma, epsilon, zeta) or calmodulin expression, or alterations in hippocampal cytoarchitecture or infrapyramidal mossy fiber limb length. Collectively, these results indicate that elevations in MARCKS expression are detrimental to specific aspects of hippocampal function.     

In vitro and in vivo effects of a novel dimeric inhibitor of PSD‐95 on excitotoxicity and functional recovery after experimental traumatic brain injury

PSD‐95 inhibitors have been shown to be neuroprotective in stroke, but have only to a very limited extent been evaluated in the treatment of traumatic brain injury (TBI) that has pathophysiological mechanisms in common with stroke. The aims of the current study were to assess the effects of a novel dimeric inhibitor of PSD‐95, UCCB01‐147, on histopathology and long‐term cognitive outcome after controlled cortical impact (CCI) in rats. As excitotoxic cell death is thought to be a prominent part of the pathophysiology of TBI, we also investigated the neuroprotective effects of UCCB01‐147 and related compounds on NMDA‐induced cell death in cultured cortical neurons. Anesthetized rats were given a CCI or sham injury, and were randomized to receive an injection of either UCCB01‐147 (10 mg/kg), the non‐competitive NMDAR‐receptor antagonist MK‐801 (1 mg/kg) or saline immediately after injury. At 2 and 4 weeks post‐trauma, spatial learning and memory were assessed in a water maze, and at 3 months, brains were removed for estimation of lesion volumes. Overall, neither treatment with UCCB01‐147 nor MK‐801 resulted in significant improvements of cognition and histopathology after CCI. Although MK‐801 provided robust neuroprotection against NMDA‐induced toxicity in cultured cortical neurons, UCCB01‐147 failed to reduce cell death and became neurotoxic at high doses. The data suggest potential differential effects of PSD‐95 inhibition in stroke and TBI that should be investigated further in future studies taking important experimental factors such as timing of treatment, dosage, and anesthesia into consideration.     

Acyl ghrelin improves cognition,synaptic plasticity deficits and neuroinflammation following amyloid β (Aβ1‐40) administration in mice

Ghrelin is a metabolic hormone that has neuroprotective actions in a number of neurological conditions, including Parkinson's disease (PD), stroke and traumatic brain injury. Acyl ghrelin treatment in vivo and in vitro also shows protective capacity in Alzheimer's disease (AD). In the present study, we used ghrelin knockout (KO) and their wild‐type littermates to test whether or not endogenous ghrelin is protective in a mouse model of AD, in which human amyloid β peptide 1‐40 (Aβ_1‐40) was injected into the lateral ventricles i.c.v. Recognition memory, using the novel object recognition task, was significantly impaired in ghrelin KO mice and after i.c.v. Aβ_1‐40 treatment. These deficits could be prevented by acyl ghrelin injections for 7 days. Spatial orientation, as assessed by the Y‐maze task, was also significantly impaired in ghrelin KO mice and after i.c.v. Aβ_1‐40 treatment. These deficits could be prevented by acyl ghrelin injections for 7 days. Ghrelin KO mice had deficits in olfactory discrimination; however, neither i.c.v. Aβ_1‐40 treatment, nor acyl ghrelin injections affected olfactory discrimination. We used stereology to show that ghrelin KO and Aβ_1‐40 increased the total number of glial fibrillary acidic protein expressing astrocytes and ionised calcium‐binding adapter expressing microglial in the rostral hippocampus. Finally, Aβ_1‐40 blocked long‐term potentiation induced by high‐frequency stimulation and this effect could be acutely blocked with co‐administration of acyl ghrelin. Collectively, our studies demonstrate that ghrelin deletion affects memory performance and also that acyl ghrelin treatment may delay the onset of early events of AD. This supports the idea that acyl ghrelin treatment may be therapeutically beneficial with respect to restricting disease progression in AD.     

Marked accumulation of oligodendroglia‐like cells in temporal lobe epilepsy with amygdala enlargement and hippocampal sclerosis

Although an increasing number of cases of temporal lobe epilepsy (TLE) with ipsilateral amygdala enlargement (AE) have been reported, there are few pathological reports, and no clear consensus has been established. Oligodendroglia or oligodendroglia‐like cells (OLCs) have recently attracted attention in epilepsy studies. Here, we report the clinical and pathological findings of a 40‐year‐old male TLE patient with AE and hippocampal sclerosis, in whom histopathological study demonstrated remarkable clustering of OLCs around the uncus. The patient began to have refractory seizures at the age of 14, and preoperative MRI revealed left amygdala enlargement and left hippocampal atrophy. Other examinations were consistent with left mesial temporal epileptogenicity. He underwent surgical resection and achieved seizure freedom. Histopathological study of the amygdala showed swollen neurons with relatively large bodies and thick neurites, accompanied by vacuolar degeneration in the background. Additionally, there were marked clusters of OLCs with round nuclei and densely stained chromatin around the uncus. The OLCs were Olig2‐positive. In the hippocampus, severe cell loss in CA1 and granule cell dispersion in the dentate gyrus were found. These findings may provide some insights for further pathological investigations of TLE with non‐neoplastic AE.     

The M‐current inhibitor XE991 decreases the stimulation threshold for long‐term synaptic plasticity in healthy mice and in models of cognitive disease

Aging, mental retardation, number of psychiatric and neurological disorders are all associated with learning and memory impairments. As the underlying causes of such conditions are very heterogeneous, manipulations that can enhance learning and memory in mice under different circumstances might be able to overcome the cognitive deficits in patients. The M‐current regulates neuronal excitability and action potential firing, suggesting that its inhibition may increase cognitive capacities. We demonstrate that XE991, a specific M‐current blocker, enhances learning and memory in healthy mice. This effect may be achieved by altering basal hippocampal synaptic activity and by diminishing the stimulation threshold for long‐term changes in synaptic efficacy and learning‐related gene expression. We also show that training sessions regulate the M‐current by transiently decreasing the levels of KCNQ/Kv7.3 protein, a pivotal subunit for the M‐current. Furthermore, we found that XE991 can revert the cognitive impairment associated with acetylcholine depletion and the neurodegeneration induced by kainic acid. Together, these results show that inhibition of the M‐current as a general strategy may be useful to enhance cognitive capacities in healthy and aging individuals, as well as in those with neurodegenerative diseases. © 2009 Wiley‐Liss, Inc.