Induction Of Long-term Potentiation Research Articles

SRC3 acetylates calmodulin in the mouse brain to regulate synaptic plasticity and fear learning

Protein acetylation is a reversible posttranslational modification, which is regulated by lysine acetyltransferase (KAT) and lysine deacetyltransferase (KDAC). Although protein acetylation has been shown to regulate synaptic plasticity, this was mainly for histone protein acetylation. The function and regulation of nonhistone protein acetylation in synaptic plasticity and learning remain largely unknown. Calmodulin (CaM), a ubiquitous Ca2+ sensor, plays critical roles in synaptic plasticity such as long-term potentiation (LTP). During LTP induction, activation of NMDA receptor triggers Ca2+ influx, and the Ca2+ binds with CaM and activates calcium/calmodulin-dependent protein kinase IIα (CaMKIIα). In our previous study, we demonstrated that acetylation of CaM was important for synaptic plasticity and fear learning in mice. However, the KAT responsible for CaM acetylation is currently unknown. Here, following an HEK293 cell-based screen of candidate KATs, steroid receptor coactivator 3 (SRC3) is identified as the most active KAT for CaM. We further demonstrate that SRC3 interacts with and acetylates CaM in a Ca2+ and NMDA receptor-dependent manner. We also show that pharmacological inhibition or genetic downregulation of SRC3 impairs CaM acetylation, synaptic plasticity, and contextual fear learning in mice. Moreover, the effects of SRC3 inhibition on synaptic plasticity and fear learning could be rescued by 3KQ-CaM, a mutant form of CaM, which mimics acetylation. Together, these observations demonstrate that SRC3 acetylates CaM and regulates synaptic plasticity and learning in mice.

Acetylation of calmodulin regulates synaptic plasticity and fear learning

Synaptic plasticity is critical for brain function, including learning and memory. It is regulated by gene transcription and protein synthesis as well as posttranslational modifications at synapses. Although protein acetylation has been shown to be involved in the regulation of synaptic plasticity, this was mainly for histone protein acetylation. To investigate whether acetylation of nonhistone proteins is important for synaptic plasticity, we analyzed mouse brain acetylome and found that calmodulin (CaM), a ubiquitous Ca2+ sensor, was acetylated on three lysine residues, which were conserved across species. NMDA receptor-dependent long-term potentiation (LTP) is considered the most compelling form of synaptic plasticity. During LTP induction, activation of NMDA receptor triggers Ca2+ influx, and the Ca2+ binds with CaM and activates calcium/calmodulin-dependent protein kinase IIα (CaMKIIα), which is essential for LTP induction. By using home-generated and site-specific antibodies against acetylated CaM, we show that CaM acetylation is upregulated by neural activities in an NMDA receptor-dependent manner. Moreover, mutation of acetyllysines in CaM1 proteins disrupts synaptic plasticity and fear learning in a mouse model. We further demonstrate that acetylation of CaM reduces the binding free energy and increases the binding affinity toward CaMKIIα, a protein kinase pivotal to synaptic plasticity and learning. Taken together, our results demonstrate importance of CaM acetylation in regulating synaptic plasticity and learning.

Intermittent Hypoxia causes targeted disruption to NMDA receptor dependent synaptic plasticity in area CA1 of the hippocampus

Changed NMDA receptor (NMDAr) physiology is implicated with cognitive deficit resulting from conditions ranging from normal aging to neurological disease. Using intermittent hypoxia (IH) to experimentally model untreated sleep apnea, a clinical condition whose comorbidities include neurocognitive impairment, we recently demonstrated that IH causes a pro-oxidant condition that contributes to deficits in spatial memory and in NMDAr-dependent long-term potentiation (LTP). However, the impact of IH on additional forms of synaptic plasticity remains ill-defined. Here we show that IH prevents the induction of NMDAr-dependent LTP and long-term depression (LTD) in hippocampal brain slices from mice exposed to ten days of IH (IH10) yet spares NMDAr-independent forms of synaptic plasticity. Deficits in synaptic plasticity were accompanied by a reduction in hippocampal GluN1 expression. Acute manipulation of redox state using the reducing agent, Dithiothreitol (DTT) stimulated the NMDAr-dependent fEPSP following IH10. However, acute use of either DTT or MnTMPyP did not restore NMDAr-dependent synaptic plasticity after IH10 or prevent the IH-dependent reduction in GluN1, the obligatory subunit of the NMDAr. In contrast, MnTMPyP during IH10 (10-MnTMPyP), prevented the suppressive effects of IH on both NMDAr-dependent synaptic plasticity and GluN1 expression. These findings indicate that while the IH-dependent pro-oxidant state causes reversible oxidative neuromodulation of NMDAr activity, acute manipulation of redox state is ineffective in rescuing two key effects of IH related to the NMDAr within the hippocampus. These IH-dependent changes associated with the NMDAr may be a primary avenue by which IH enhances the vulnerability to impaired learning and memory when sleep apnea is left untreated in normal aging and in disease.

Comparing the effects of crocin at different doses on excitability and long-term potentiation in the CA1 area, as well as the electroencephalogram responses of rats under chronic stress.

Stress adversely affects the cellular and electrophysiological mechanisms of memory; however, crocin has beneficial effects on brain functions. Nonetheless, the electrophysiological effects of using this active saffron component at different doses are not yet studied in rats under chronic restraint stress. Therefore, this study compared the impact of crocin at different doses on the excitability and long-term potentiation(LTP) in the CA1 area of rats, as well as their electroencephalogram(EEG) responses, hippocampal and frontal cortical glucose levels under chronic restraint stress (an emotional stress model).Forty rats were allocated into five groups of control, sham, restraint stress (6h/day/21days), and two stress groups receiving intraperitoneal injections of crocin (30, 60mg/kg/day). Besides measuring the slope and amplitude of field excitatory postsynaptic potentials(fEPSPs) in the input-output and LTP curves, the EEG waves and hippocampal and frontal cortical glucose levels were assessed in all groups.Chronic restraint stress significantly decreased the fEPSP slope and amplitude in the input-output curves and after LTP induction. Both doses of crocin (60and particularly 30mg/kg) significantly improved fEPSP slope and amplitude in the stressed groups. Also, stress and crocin only at a dose of 30mg/kg altered the EEG waves. Hippocampal and frontal cortical glucose levels displayed no significant differences in the experimental groups.Crocin at doses of 60mg/kg/day and particularly 30mg/kg/day reversed the harmful effects of chronic restraint stress on LTP as a cellular memory-related mechanism. However, only the lower dose of crocin affected the electrical brain activity in EEG.

Therapeutic Ultrasound as a Treatment Modality for Physiological and Pathological Ageing Including Alzheimer's Disease.

Physiological and pathological ageing (as exemplified by Alzheimer’s disease, AD) are characterized by a progressive decline that also includes cognition. How this decline can be slowed or even reversed is a critical question. Here, we discuss therapeutic ultrasound as a novel modality to achieve this goal. In our studies, we explored three fundamental strategies, (i) scanning ultrasound on its own (SUSonly), (ii) therapeutic ultrasound in concert with intravenously injected microbubbles (which transiently opens the blood–brain barrier, SUS+MB), and (iii) SUS+MB in combination with therapeutic antibodies (SUS+MB+mAb). These studies show SUS+MB effectively clears amyloid and restores memory in amyloid-depositing mice and partially clears Tau and ameliorates memory impairments in Tau transgenic mice, with additional improvements found in combination trials (SUS+MB+mAb). Interestingly, both SUSonly and SUS+MB restored the induction of long-term potentiation (LTP, electrophysiological correlate of memory) in senescent wild-type mice. Both lead to increased neurogenesis, and SUSonly, in particular, resulted in improved spatial memory. We discuss these findings side-by-side with our findings obtained in AD mouse models. We conclude that therapeutic ultrasound is a non-invasive, pleiotropic modality that may present a treatment option not only for AD but also for enhancing cognition in physiological ageing.

Role of N-methyl-d-aspartate receptor subunits GluN2A and GluN2B in auditory thalamocortical long-term potentiation in adult mice

Cortical neurons undergo continuous remodelling throughout development and into adulthood, associated with long-term changes in the synaptic transmission of thalamocortical pathways, i.e., long-term potentiation (LTP); such plasticity is input-specific, reflected in the frequency-specificity of the auditory system. It is well established that thalamocortical LTP is dependent on the activation of N-methyl-d-aspartate (NMDA) receptors. In this study, the roles of NMDA receptor subunits GluN2A and GluN2B in LTP induction were examined in thalamocortical pathways of the auditory system using subunit-selective pharmacological inhibition and in vivo tetanic stimulation of the auditory thalamus, while recording neural response in the primary auditory cortex. Long-term enhancement of thalamocortical field excitatory postsynaptic potentials (i.e., thalamocortical LTP) were induced by high frequency tetanic stimulation of the ventral division of the medial geniculate body. Such enhancement in thalamocortical fEPSPs was decreased when a GluN2A blocker (NVP-M077) was applied to the recording site in the primary auditory cortex and was increased when a GluN2B blocker (Ro25-6981) was applied. Our data suggest that the induction of thalamocortical LTP is dependent on the differential expression of the GluN2A and GluN2B subunits of NMDA receptors in thalamocortical circuits.

Treatment with edaravone improves the structure and functional changes in the hippocampus after chronic cerebral hypoperfusion in rat

This study aimed to find out cellular and electrophysiological effects of the edaravone (EDR) administration following induction of vascular dementia (VaD) via bilateral-carotid vessel occlusion (2VO).The rats were randomly divided into control, sham, 2VO + V (vehicle), and 2VO + EDR groups. EDR was administered once a day from day 0–28 after surgery. The passive-avoidance, Morris water-maze, and open-field tests were used for evaluation of memory, locomotor, and anxiety. The field-potential recording was used for assessment of electrophysiological properties of the hippocampus; and after sacrificing, the cerebral hemispheres were removed for stereological study and evaluation of MDA levels. The long-term potentiation (LTP), paired-pulse ratio (PPR), and input-output (I/O) curves were evaluated as indexes for long-term and short-term synaptic plasticity, and basal-synaptic transmission (BST), respectively.The 2VO led to increases in MDA level with considerable neuronal loss and decreases in the volume of the hippocampus, along with a reduction in the BST and LTP induction which was associated with a decrement in PPR and ultimate loss in memory with higher anxiety behavior. However, administration of EDR caused a decline in MDA and prevented the neural loss and volume of the hippocampus, rescued BST and LTP depression, improved memory and anxiety without any effects on PPR.Therefore, most likely through the improvement of MDA level, and the hippocampal cell number and volume, EDR leads to recovery of synaptic plasticity and behavioral performance. Because of the LTP rescue, without recovery of PPR, it is likely that the EDR improved LTP through the post-synaptic neurons.

Nitric Oxide Regulates GluA2-Lacking AMPAR Contribution to Synaptic Transmission of CA1 Apical but Not Basal Dendrites.

The mechanisms of synaptic plasticity differ in distinct local circuits. In the CA1 region of the hippocampus, the mechanisms of long-term potentiation (LTP) at apical dendrites in stratum radiatum and basal dendrites in stratum oriens involve different molecular cascades. For instance, participation of nitric oxide in LTP induction was shown to be necessary only for apical dendrites. This phenomenon may play a key role in information processing in CA1, and one of the reasons for this difference may be differing synaptic characteristics in these regions. Here, we compared the synaptic responses to stimulation of apical and basal dendrites of CA1 pyramidal neurons and found a difference in the current–voltage characteristics of these inputs, which is presumably due to a distinct contribution of GluA2-lacking AMPA receptors to synaptic transmission. In addition, we obtained data that indicate the presence of these receptors in pyramidal dendrites in both stratum radiatum and stratum oriens. We also demonstrated that inhibition of NO synthase reduced the contribution of GluA2-lacking AMPA receptors at apical but not basal dendrites, and inhibition of soluble guanylate cyclase did not affect this phenomenon.

Low-intensity ultrasound restores long-term potentiation and memory in senescent mice through pleiotropic mechanisms including NMDAR signaling

Advanced physiological aging is associated with impaired cognitive performance and the inability to induce long-term potentiation (LTP), an electrophysiological correlate of memory. Here, we demonstrate in the physiologically aged, senescent mouse brain that scanning ultrasound combined with microbubbles (SUS+MB), by transiently opening the blood–brain barrier, fully restores LTP induction in the dentate gyrus of the hippocampus. Intriguingly, SUS treatment without microbubbles (SUSonly), i.e., without the uptake of blood-borne factors, proved even more effective, not only restoring LTP, but also ameliorating the spatial learning deficits of the aged mice. This functional improvement is accompanied by an altered milieu of the aged hippocampus, including a lower density of perineuronal nets, increased neurogenesis, and synaptic signaling, which collectively results in improved spatial learning. We therefore conclude that therapeutic ultrasound is a non-invasive, pleiotropic modality that may enhance cognition in elderly humans.

KIF13A drives AMPA receptor synaptic delivery for long-term potentiation via endosomal remodeling.

The regulated trafficking of AMPA-type glutamate receptors (AMPARs) from dendritic compartments to the synaptic membrane in response to neuronal activity is a core mechanism for long-term potentiation (LTP). However, the contribution of the microtubule cytoskeleton to this synaptic transport is still unknown. In this work, using electrophysiological, biochemical, and imaging techniques, we have found that one member of the kinesin-3 family of motor proteins, KIF13A, is specifically required for the delivery of AMPARs to the spine surface during LTP induction. Accordingly, KIF13A depletion from hippocampal slices abolishes LTP expression. We also identify the vesicular protein centaurin-α1 as part of a motor transport machinery that is engaged with KIF13A and AMPARs upon LTP induction. Finally, we determine that KIF13A is responsible for the remodeling of Rab11-FIP2 endosomal structures in the dendritic shaft during LTP. Overall, these results identify specific kinesin molecular motors and endosomal transport machinery that catalyzes the dendrite-to-synapse translocation of AMPA receptors during synaptic plasticity.

Endophilin A1 drives acute structural plasticity of dendritic spines in response to Ca2+/calmodulin.

Induction of long-term potentiation (LTP) in excitatory neurons triggers a large transient increase in the volume of dendritic spines followed by decays to sustained size expansion, a process termed structural LTP (sLTP) that contributes to the cellular basis of learning and memory. Although mechanisms regulating the early and sustained phases of sLTP have been studied intensively, how the acute spine enlargement immediately after LTP stimulation is achieved remains elusive. Here, we report that endophilin A1 orchestrates membrane dynamics with actin polymerization to initiate spine enlargement in NMDAR-mediated LTP. Upon LTP induction, Ca2+/calmodulin enhances binding of endophilin A1 to both membrane and p140Cap, a cytoskeletal regulator. Consequently, endophilin A1 rapidly localizes to the plasma membrane and recruits p140Cap to promote local actin polymerization, leading to spine head expansion. Moreover, its molecular functions in activity-induced rapid spine growth are required for LTP and long-term memory. Thus, endophilin A1 serves as a calmodulin effector to drive acute structural plasticity necessary for learning and memory.

Serine/Threonine Phosphatases in LTP: Two B or Not to Be the Protein Synthesis Blocker-Induced Impairment of Early Phase.

Dephosphorylation of target proteins at serine/threonine residues is one of the most crucial mechanisms regulating their activity and, consequently, the cellular functions. The role of phosphatases in synaptic plasticity, especially in long-term depression or depotentiation, has been reported. We studied serine/threonine phosphatase activity during the protein synthesis blocker (PSB)-induced impairment of long-term potentiation (LTP). Established protein phosphatase 2B (PP2B, calcineurin) inhibitor cyclosporin A prevented the LTP early phase (E-LTP) decline produced by pretreatment of hippocampal slices with cycloheximide or anisomycin. For the first time, we directly measured serine/threonine phosphatase activity during E-LTP, and its significant increase in PSB-treated slices was demonstrated. Nitric oxide (NO) donor SNAP also heightened phosphatase activity in the same manner as PSB, and simultaneous application of anisomycin + SNAP had no synergistic effect. Direct measurement of the NO production in hippocampal slices by the NO-specific fluorescent probe DAF-FM revealed that PSBs strongly stimulate the NO concentration in all studied brain areas: CA1, CA3, and dentate gyrus (DG). Cyclosporin A fully abolished the PSB-induced NO production in the hippocampus, suggesting a close relationship between nNOS and PP2B activity. Surprisingly, cyclosporin A alone impaired short-term plasticity in CA1 by decreasing paired-pulse facilitation, which suggests bi-directionality of the influences of PP2B in the hippocampus. In conclusion, we proposed a minimal model of signaling events that occur during LTP induction in normal conditions and the PSB-treated slices.

Losartan improved hippocampal long-term potentiation impairment induced by repeated LPS injection in rats.

Cognitive impairment has been known as a common consequence of brain inflammation. Long‐term potentiation (LTP), the generally accepted cellular mechanism for memory formation in the mammalian brain, has been shown to be suppressed by inflammation. Studies have shown that angiotensin II (Ang II) through the Ang II type 1 receptor (AT1R) has a role in brain and peripheral immune system communication and brain inflammation. Here, the effect of AT1R blockade on hippocampal LTP in rats undergoing repeated lipopolysaccharide (LPS) injection was investigated. Rats received intraperitoneal (ip) injections of LPS (250 μg kg−1 day−1) for seven days. Treatment with losartan (ip; 3 mg kg−1 day−1) was started 3 days before LPS injection and continued during the LPS injections. Rats were anesthetized, and field excitatory postsynaptic potential (fEPSP) was recorded from the stratum radiatum of the CA1 area of the hippocampus in response to stimulation of the Schaffer collateral pathway. Results showed that LTP was suppressed in the LPS‐injected rats as no significant differences were found in the fEPSP slope and amplitude before and after the LTP induction. AT1R blockade by losartan restored fEPSP to the control levels. These findings indicate that Ang II, through AT1R, has a role in LTP suppression induced by systemic inflammation.

Abscisic acid interplays with PPARγ receptors and ameliorates diabetes-induced cognitive deficits in rats.

This study intended to evaluate if central administration of abscisic acid (ABA) alone or in combination with GW9662, a peroxisome proliferator-activated receptor γ (PPAR-γ) antagonist, could modulate learning and memory as well as hippocampal synaptic plasticity in a rat model of streptozotocin (STZ)-induced diabetes. Intraperitonealinjectionof STZ (65 mg/kg) was used to induce diabetes. Diabetic rats were than treated with intracerebroventricular (i.c.v.) administration of ABA (10, 15 and 20 µg/rat), GW9662 (3 µg/rat) or GW9662 (3 µg/rat) plus ABA (20 µg/rat). Animals' spatial and passive avoidance learning and memory performances were assessed by Morris water maze (MWM) and shuttle box tasks, respectively. Further, in vivo electrophysiologicalfield recordings were assessed in the CA1 region. STZ diabetic rats showed diminished learning and memory in both MWM and shuttle box tasks. The STZ-induced memory deficits were attenuated by central infusion of ABA (10 and 20 µg/rat). Besides, STZ injection impaired long-term potentiationinduction in CA1 neurons that was attenuated by ABA at 20 μg/rat. Central administration of GW9662 (3 µg/rat) alone did not modify STZ-induced spatial and passive avoidance learning and memory performances of rats. Further, GW9662 prevented ABA capacity to restore learning and memory in behavioral and electrophysiology trials. Altogether, ABA ameliorates cognitive deficits in rats via activation of PPAR-γ receptor in diabetic rats.

TRPM4 Expression During Postnatal Developmental of Mouse CA1 Pyramidal Neurons.

TRPM4 is a non-selective cation channel activated by intracellular calcium and permeable to monovalent cations. This channel participates in the control of neuronal firing, neuronal plasticity, and neuronal death. TRPM4 depolarizes dendritic spines and is critical for the induction of NMDA receptor-dependent long-term potentiation in CA1 pyramidal neurons. Despite its functional importance, no subcellular localization or expression during postnatal development has been described in this area. To examine the localization and expression of TRPM4, we performed duplex immunofluorescence and patch-clamp in brain slices at different postnatal ages in C57BL/6J mice. At P0 we found TRPM4 is expressed with a somatic pattern. At P7, P14, and P35, TRPM4 expression extended from the soma to the apical dendrites but was excluded from the axon initial segment. Patch-clamp recordings showed a TRPM4-like current active at the resting membrane potential from P0, which increased throughout the postnatal development. This current was dependent on intracellular Ca2+ (ICAN) and sensitive to 9-phenanthrol (9-Ph). Inhibiting TRPM4 with 9-Ph hyperpolarized the membrane potential at P14 and P35, with no effect in earlier stages. Together, these results show that TRPM4 is expressed in CA1 pyramidal neurons in the soma and apical dendrites and associated with a TRPM4-like current, which depolarizes the neurons. The expression, localization, and function of TRPM4 throughout postnatal development in the CA1 hippocampal may underlie an important mechanism of control of membrane potential and action potential firing during critical periods of neuronal development, particularly during the establishment of circuits.

Stress-Induced Enhanced Long-Term Potentiation and Reduced Threshold for N-Methyl-D-Aspartate Receptor- and β-Adrenergic Receptor-Mediated Synaptic Plasticity in Rodent Ventral Subiculum.

Stress is a biologically relevant signal and can modulate hippocampal synaptic plasticity. The subiculum is the major output station of the hippocampus and serves as a critical hub in the stress response network. However, stress-associated synaptic plasticity in the ventral subiculum has not been adequately addressed. Therefore, we investigated the impact of a single exposure to an inherently stressful two-way active avoidance conditioning on the induction of long-term potentiation (LTP) at CA1—subiculum synapses in ventral hippocampal slices from young adult rats 1 day after stressor exposure. We found that acute stress enhanced LTP and lowered the induction threshold for a late-onset LTP at excitatory CA1 to subicular burst-spiking neuron synapses. This late-onset LTP was dependent on the activation of β-adrenergic and glutamatergic N-methyl-D-aspartate receptors and independent of D1/D5 dopamine receptor activation. Thereby, we present a cellular mechanism that might contribute to behavioral stress adaptation after acute stressor exposure.

Optogenetic induction of orbitostriatal long-term potentiation in the dorsomedial striatum elicits a persistent reduction of alcohol-seeking behavior in rats

Uncontrolled drug-seeking and -taking behaviors are generally driven by maladaptive corticostriatal synaptic plasticity. The orbital frontal cortex (OFC) and its projections to the dorsomedial striatum (DMS) have been extensively implicated in drug-seeking and relapse behaviors. The influence of the synaptic plasticity of OFC projections to the DMS (OFC→DMS) on drug-seeking and -taking behaviors has not been fully characterized. To investigate this, we trained rats to self-administer 20% alcohol and then delivered an in vivo optogenetic protocol designed to induce long-term potentiation (LTP) selectively at OFC→DMS synapses. We selected LTP induction because we found that voluntary alcohol self-administration suppressed OFC→DMS transmission and LTP may normalize this transmission, consequently reducing alcohol-seeking behavior. Importantly, ex vivo slice electrophysiology studies confirmed that this in vivo optical stimulation protocol resulted in a significant increase in excitatory OFC→DMS transmission strength on day two after stimulation, suggesting that LTP was induced in vivo. Rat alcohol-seeking and -taking behaviors were significantly reduced on days 1–3, but not on days 7–11, after LTP induction. Striatal synaptic plasticity is modulated by several critical neurotransmitter receptors, including dopamine D1 receptors (D1Rs) and adenosine A2A receptors (A2ARs). We found that delivery of in vivo optical stimulation in the presence of a D1R antagonist abolished the LTP-associated decrease in alcohol-seeking behavior, whereas delivery in the presence of an A2AR antagonist may facilitate this LTP-induced behavioral change. These results demonstrate that alcohol-seeking behavior was negatively regulated by the potentiation of excitatory OFC→DMS neurotransmission. Our findings provide direct evidence that the OFC exerts “top-down” control of alcohol-seeking behavior via the DMS.

Neurogranin Regulates Adult-Born Olfactory Granule Cell Spine Density and Odor-Reward Associative Memory in Mice

Neurogranin (Ng) is a brain-specific postsynaptic protein, whose role in modulating Ca2+/calmodulin signaling in glutamatergic neurons has been linked to enhancement in synaptic plasticity and cognitive functions. Accordingly, Ng knock-out (Ng-ko) mice display hippocampal-dependent learning and memory impairments associated with a deficit in long-term potentiation induction. In the adult olfactory bulb (OB), Ng is expressed by a large population of GABAergic granule cells (GCs) that are continuously generated during adult life, undergo high synaptic remodeling in response to the sensory context, and play a key role in odor processing. However, the possible implication of Ng in OB plasticity and function is yet to be investigated. Here, we show that Ng expression in the OB is associated with the mature state of adult-born GCs, where its active-phosphorylated form is concentrated at post-synaptic sites. Constitutive loss of Ng in Ng-ko mice resulted in defective spine density in adult-born GCs, while their survival remained unaltered. Moreover, Ng-ko mice show an impaired odor-reward associative memory coupled with reduced expression of the activity-dependent transcription factor Zif268 in olfactory GCs. Overall, our data support a role for Ng in the molecular mechanisms underlying GC plasticity and the formation of olfactory associative memory.

Physiological role for GABAA receptor desensitization in the induction of long-term potentiation at inhibitory synapses

GABAA receptors (GABAARs) are pentameric ligand-gated ion channels distributed throughout the brain where they mediate synaptic and tonic inhibition. Following activation, these receptors undergo desensitization which involves entry into long-lived agonist-bound closed states. Although the kinetic effects of this state are recognised and its structural basis has been uncovered, the physiological impact of desensitization on inhibitory neurotransmission remains unknown. Here we describe an enduring form of long-term potentiation at inhibitory synapses that elevates synaptic current amplitude for 24 h following desensitization of GABAARs in response to agonist exposure or allosteric modulation. Using receptor mutants and allosteric modulators we demonstrate that desensitization of GABAARs facilitates their phosphorylation by PKC, which increases the number of receptors at inhibitory synapses. These observations provide a physiological relevance to the desensitized state of GABAARs, acting as a signal to regulate the efficacy of inhibitory synapses during prolonged periods of inhibitory neurotransmission.

Blockade of Motor Cortical Long-Term Potentiation Induction by Glutamatergic Dysfunction Causes Abnormal Neurobehavior in an Experimental Subarachnoid Hemorrhage Model.

Subarachnoid hemorrhage (SAH) is a life-threatening condition that can also lead to permanent paralysis. However, the mechanisms that underlying neurobehavioral deficits after SAH have not been fully elucidated. As theta burst stimulation (TBS) can induce long-term potentiation (LTP) in the motor cortex, we tested its potential as a functional evaluation tool after experimentally induced SAH. Motor cortical inter-neuronal excitability was evaluated in anesthetized rats after 200 Hz-quadripulse TBS (QTS5), 200 Hz-quadripulse stimulation (QPS5), and 400 Hz-octapulse stimulation (OPS2.5). Furthermore, correlation between motor cortical LTP and N-methyl-D-aspartate-receptor activation was evaluated using MK-801, a NMDA-receptor antagonist. We evaluated inhibition-facilitation configurations [interstimulus interval: 3 ms; short-latency intracortical inhibition (SICI) and 11 ms; intracortical facilitation (ICF)] with paired electrical stimulation protocols and the effect of TBS paradigm on continuous recording of motor-evoked potentials (MEPs) for quantitative parameters. SAH and MK-801 completely blocked ICF, while SICI was preserved. QTS5, QPS5, and OPS2.5 facilitated continuous MEPs, persisting for 180 min. Both SAH and MK-801 completely blocked MEP facilitations after QPS5 and OPS2.5, while MEP facilitations after QTS5 were preserved. Significant correlations were found among neurological scores and 3 ms-SICI rates, 11 ms-ICF rates, and MEP facilitation rates after 200 Hz-QTS5, 7 days after SAH (R2 = 0.6236; r = −0.79, R2 = 0.6053; r = −0.77 and R2 = 0.9071; r = 0.95, p < 0.05, respectively). Although these findings need to be verified in humans, our study demonstrates that the neurophysiological parameters 3 ms-SICI, 11 ms-ICF, and 200 Hz-QTS5-MEPs may be useful surrogate quantitative biomarkers for assessing inter-neuronal function after SAH.