Traditionally, hippocampal long-term potentiation (LTP) of synaptic strength requires Ca2+/calmodulin (CaM)-dependent protein kinase II (CaMKII) and other kinases, whereas long-term depression (LTD) ...requires phosphatases. Here, we found that LTD also requires CaMKII and its phospho-T286-induced “autonomous” (Ca2+-independent) activity. However, whereas LTP is known to induce phosphorylation of the AMPA-type glutamate receptor (AMPAR) subunit GluA1 at S831, LTD instead induced CaMKII-mediated phosphorylation at S567, a site known to reduce synaptic GluA1 localization. GluA1 S831 phosphorylation by “autonomous” CaMKII was further stimulated by Ca2+/CaM, as expected for traditional substrates. By contrast, GluA1 S567 represents a distinct substrate class that is unaffected by such stimulation. This differential regulation caused GluA1 S831 to be favored by LTP-type stimuli (strong but brief), whereas GluA1 S567 was favored by LTD-type stimuli (weak but prolonged). Thus, requirement of autonomous CaMKII in opposing forms of plasticity involves distinct substrate classes that are differentially regulated to enable stimulus-dependent substrate-site preference.
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•Autonomous CaMKII activity is required not only for LTP, but also for LTD•LTP stimuli (strong but brief) favor traditional substrate site phosphorylation•LTD stimuli (weak but prolonged) instead favor a distinct substrate class•Deciding factor in substrate choice is further Ca2+/CaM stimulation of CaMKII
CaMKII and its “autonomous” activity, induced by T286-autophosphorylation, is a crucial mediator of long-term potentiation (LTP) of synaptic strength. In this study, Dell’Acqua, Bayer, and colleagues show that this CaMKII autonomy is also required for long-term depression (LTD), an opposing form of synaptic plasticity. These opposing functions involve stimulus-dependent differential substrate site selection on GluA1: S831 (a traditional substrate favored by LTP-type stimuli) versus S567 (a distinct substrate class instead favored by LTD-type stimuli).
Regulated insertion and removal of postsynaptic AMPA glutamate receptors (AMPARs) mediates hippocampal long-term potentiation (LTP) and long-term depression (LTD) synaptic plasticity underlying ...learning and memory. In Alzheimer’s disease β-amyloid (Aβ) oligomers may impair learning and memory by altering AMPAR trafficking and LTP/LTD balance. Importantly, Ca2+-permeable AMPARs (CP-AMPARs) assembled from GluA1 subunits are excluded from hippocampal synapses basally but can be recruited rapidly during LTP and LTD to modify synaptic strength and signaling. By employing mouse knockin mutations that disrupt anchoring of the kinase PKA or phosphatase Calcineurin (CaN) to the postsynaptic scaffold protein AKAP150, we find that local AKAP-PKA signaling is required for CP-AMPAR recruitment, which can facilitate LTP but also, paradoxically, prime synapses for Aβ impairment of LTP mediated by local AKAP-CaN LTD signaling that promotes subsequent CP-AMPAR removal. These findings highlight the importance of PKA/CaN signaling balance and CP-AMPARs in normal plasticity and aberrant plasticity linked to disease.
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•Anchored PKA and CaN exert opposing control of CP-AMPARs at adult CA1 synapses•AKAP-PKA signaling recruits CP-AMPARs during LTP, LTD and following Aβ exposure•CP-AMPARs prime synapses for LTD and Aβ inhibition of LTP mediated by AKAP-CaN•Aβ hijacks CP-AMPAR regulation by PKA/CaN to tip LTP/LTD balance in favor of LTD
In Alzheimer’s disease, Aβ oligomers disrupt hippocampal neuronal plasticity and cognition. Sanderson et al. show how the postsynaptic scaffold protein AKAP150 coordinates PKA and Calcineurin regulation of Ca2+-permeable AMPA-type glutamate receptors to mediate disruption of synaptic plasticity by Aβ oligomers.
AMPA receptors (AMPARs) are tetrameric ion channels assembled from GluA1-GluA4 subunits that mediate the majority of fast excitatory synaptic transmission in the brain. In the hippocampus, most ...synaptic AMPARs are composed of GluA1/2 or GluA2/3 with the GluA2 subunit preventing Ca(2+) influx. However, a small number of Ca(2+)-permeable GluA1 homomeric receptors reside in extrasynaptic locations where they can be rapidly recruited to synapses during synaptic plasticity. Phosphorylation of GluA1 S845 by the cAMP-dependent protein kinase (PKA) primes extrasynaptic receptors for synaptic insertion in response to NMDA receptor Ca(2+) signaling during long-term potentiation (LTP), while phosphatases dephosphorylate S845 and remove synaptic and extrasynaptic GluA1 during long-term depression (LTD). PKA and the Ca(2+)-activated phosphatase calcineurin (CaN) are targeted to GluA1 through binding to A-kinase anchoring protein 150 (AKAP150) in a complex with PSD-95, but we do not understand how the opposing activities of these enzymes are balanced to control plasticity. Here, we generated AKAP150ΔPIX knock-in mice to selectively disrupt CaN anchoring in vivo. We found that AKAP150ΔPIX mice lack LTD but express enhanced LTP at CA1 synapses. Accordingly, basal GluA1 S845 phosphorylation is elevated in AKAP150ΔPIX hippocampus, and LTD-induced dephosphorylation and removal of GluA1, AKAP150, and PSD-95 from synapses are impaired. In addition, basal synaptic activity of GluA2-lacking AMPARs is increased in AKAP150ΔPIX mice and pharmacologic antagonism of these receptors restores normal LTD and inhibits the enhanced LTP. Thus, AKAP150-anchored CaN opposes PKA phosphorylation of GluA1 to restrict synaptic incorporation of Ca(2+)-permeable AMPARs both basally and during LTP and LTD.
Learning and memory are thought to require hippocampal long-term potentiation (LTP), and one of the few central dogmas of molecular neuroscience that has stood undisputed for more than three decades ...is that LTP induction requires enzymatic activity of the Ca
/calmodulin-dependent protein kinase II (CaMKII)
. However, as we delineate here, the experimental evidence is surprisingly far from conclusive. All previous interventions inhibiting enzymatic CaMKII activity and LTP
also interfere with structural CaMKII roles, in particular binding to the NMDA-type glutamate receptor subunit GluN2B
. Thus, we here characterized and utilized complementary sets of new opto-/pharmaco-genetic tools to distinguish between enzymatic and structural CaMKII functions. Several independent lines of evidence demonstrated LTP induction by a structural function of CaMKII rather than by its enzymatic activity. The sole contribution of kinase activity was autoregulation of this structural role via T286 autophosphorylation, which explains why this distinction has been elusive for decades. Directly initiating the structural function in a manner that circumvented this T286 role was sufficient to elicit robust LTP, even when enzymatic CaMKII activity was blocked.
CaMKII has molecular memory functions because transient calcium ion stimuli can induce long-lasting increases in its synaptic localization and calcium ion-independent (autonomous) activity, thereby ...leaving memory traces of calcium ion stimuli beyond their duration. The synaptic effects of two mechanisms that induce CaMKII autonomy are well studied: autophosphorylation at threonine-286 and binding to GluN2B. Here, we examined the neuronal functions of additional autonomy mechanisms: nitrosylation and oxidation of the CaMKII regulatory domain. We generated a knock-in mouse line with mutations that render the CaMKII regulatory domain nitrosylation/oxidation-incompetent, CaMKII
, and found that it had deficits in memory and synaptic plasticity that were similar to those in aged wild-type mice. In addition, similar to aged wild-type mice, in which CaMKII was hyponitrosylated, but unlike mice with impairments of other CaMKII autonomy mechanisms, CaMKII
mice showed reduced long-term potentiation (LTP) when induced by theta-burst stimulation but not high-frequency stimulation (HFS). As in aged wild-type mice, the HFS-LTP in the young adult CaMKII
mice required L-type voltage-gated calcium ion channels. The effects in aged mice were likely caused by the loss of nitrosylation because no decline in CaMKII oxidation was detected. In hippocampal neurons, nitrosylation of CaMKII induced its accumulation at synapses under basal conditions in a manner mediated by GluN2B binding, like after LTP stimuli. However, LTP-induced synaptic CaMKII accumulation did not require nitrosylation. Thus, an aging-associated decrease in CaMKII nitrosylation may cause impairments by chronic synaptic effects, such as the decrease in basal synaptic CaMKII.
Genetic alterations in autism spectrum disorders (ASD) frequently disrupt balance between synaptic excitation and inhibition and alter plasticity in the hippocampal CA1 region. Individuals with ...Timothy Syndrome (TS), a genetic disorder caused by CaV1.2 L-type Ca2+ channel (LTCC) gain-of function mutations, such as G406R, exhibit social deficits, repetitive behaviors, and cognitive impairments characteristic of ASD that are phenocopied in TS2-neo mice expressing G406R. Here, we characterized hippocampal CA1 synaptic function in male TS2-neo mice and found basal excitatory transmission was slightly increased and inhibitory transmission strongly decreased. We also found distinct impacts on two LTCC-dependent forms of long-term potentiation (LTP) synaptic plasticity that were not readily consistent with LTCC gain-of-function. LTP induced by high-frequency stimulation (HFS) was strongly impaired in TS2-neo mice, suggesting decreased LTCC function. Yet, CaV1.2 expression, basal phosphorylation, and current density were similar for WT and TS2-neo. However, this HFS-LTP also required GABAA receptor activity, and thus may be impaired in TS2-neo due to decreased inhibitory transmission. In contrast, LTP induced in WT mice by prolonged theta-train (PTT) stimulation in the presence of a β-adrenergic receptor agonist to increase CaV1.2 phosphorylation was partially induced in TS2-neo mice by PTT stimulation alone, consistent with increased LTCC function. Overall, our findings provide insights regarding how altered CaV1.2 channel function disrupts basal transmission and plasticity that could be relevant for neurobehavioral alterations in ASD.
This article is part of the Special Issue on ‘L-type calcium channel mechanisms in neuropsychiatric disorders’.
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•CaV1.2 G406R mutation in Timothy Syndrome decreases CA1 synaptic inhibition.•G406R inhibits L-type Ca2+ channel dependent, high-frequency stimulation/HFS-LTP.•G406R sensitizes synapses to potentiation by prolonged theta train/PTT stimulation.•G406R partially occludes β-adrenergic promotion of CaV1.2-dependent PTT-LTP.
Alcohol's deleterious effects on memory are well known. Acute alcohol-induced memory loss is thought to occur via inhibition of NMDA receptor (NMDAR)-dependent long-term potentiation in the ...hippocampus. We reported previously that ethanol inhibition of NMDAR function and long-term potentiation is correlated with a reduction in the phosphorylation of Tyr¹â´â·Â² on the NR2B subunit and ethanol's inhibition of the NMDAR field excitatory postsynaptic potential was attenuated by a broad spectrum tyrosine phosphatase inhibitor. These data suggested that ethanol's inhibitory effect may involve protein tyrosine phosphatases. Here we demonstrate that the loss of striatal-enriched protein tyrosine phosphatase (STEP) renders NMDAR function, phosphorylation, and long-term potentiation, as well as fear conditioning, less sensitive to ethanol inhibition. Moreover, the ethanol inhibition was "rescued" when the active STEP protein was reintroduced into the cells. Taken together, our data suggest that STEP contributes to ethanol inhibition of NMDAR function via dephosphorylation of tyrosine sites on NR2B receptors and lend support to the hypothesis that STEP may be required for ethanol's amnesic effects.
Previously, we found that amyloid-beta (Aβ) competitively inhibits the kinesin motor protein KIF11 (Kinesin-5/Eg5), leading to defects in the microtubule network and in neurotransmitter and ...neurotrophin receptor localization and function. These biochemical and cell biological mechanisms for Aβ-induced neuronal dysfunction may underlie learning and memory defects in Alzheimer’s disease (AD). Here, we show that KIF11 overexpression rescues Aβ-mediated decreases in dendritic spine density in cultured neurons and in long-term potentiation in hippocampal slices. Furthermore, Kif11 overexpression from a transgene prevented spatial learning deficits in the 5xFAD mouse model of AD. Finally, increased KIF11 expression in neuritic plaque-positive AD patients’ brains was associated with better cognitive performance and higher expression of synaptic protein mRNAs. Taken together, these mechanistic biochemical, cell biological, electrophysiological, animal model, and human data identify KIF11 as a key target of Aβ-mediated toxicity in AD, which damages synaptic structures and functions critical for learning and memory in AD.
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•Cognitive deficits in 5xFAD mice are prevented by Kif11 overexpression•Kif11 overexpression prevents deficits in long-term potentiation in 5xFAD mice•Aβ-mediated dendritic spine loss is blocked by Kif11 overexpression•Higher KIF11 expression in brain correlates with better cognition in AD patients
Pathophysiology; Cellular neuroscience; Cell biology.
Alzheimer's disease (AD) is characterized by neurofibrillary tangles, amyloid plaques, and neurodegeneration. However, this pathology is preceded by increased soluble amyloid beta (Aβ) 1-42 oligomers ...that interfere with the glutamatergic synaptic plasticity required for learning and memory, includingN-methyl-d-aspartate receptor (NMDAR)-dependent long-term potentiation (LTP). In particular, soluble Aβ(1-42) acutely inhibits LTP and chronically causes synapse loss. Many mechanisms have been proposed for Aβ-induced synaptic dysfunction, but we recently found that Aβ(1-42) inhibits the microtubule motor protein Eg5/kinesin-5. Here we compared the impacts of Aβ(1-42) and monastrol, a small-molecule Eg5 inhibitor, on LTP in hippocampal slices and synapse loss in neuronal cultures. Acute (20-minute) treatment with monastrol, like Aβ, completely inhibited LTP at doses >100 nM. In addition, 1 nM Aβ(1-42) or 50 nM monastrol inhibited LTP #x223c;50%, and when applied together caused complete LTP inhibition. At concentrations that impaired LTP, neither Aβ(1-42) nor monastrol inhibited NMDAR synaptic responses until #x223c;60 minutes, when only #x223c;25% inhibition was seen for monastrol, indicating that NMDAR inhibition was not responsible for LTP inhibition by either agent when applied for only 20 minutes. Finally, 48 hours of treatment with either 0.5-1.0μM Aβ(1-42) or 1-5μM monastrol reduced the dendritic spine/synapse density in hippocampal cultures up to a maximum of #x223c;40%, and when applied together at maximal concentrations, no additional spine loss resulted. Thus, monastrol can mimic and in some cases occlude the impact of Aβon LTP and synapse loss, suggesting that Aβinduces acute and chronic synaptic dysfunction in part through inhibiting Eg5.
This commentary discusses the important contributions of the article published in this journal by Huang and colleagues, titled, “Acute ethanol exposure increases firing and induces oscillations in ...cerebellar Golgi cells of freely moving rats.” In this manuscript, Huang and colleagues present a number of interesting and important findings. While it has been shown previously that ethanol (EtOH) causes an increase in the firing of cerebellar Golgi cells in brain slice preparations and anesthetized animals, here the authors provide the first evidence that this action of EtOH occurs in vivo in freely moving, unanesthetized animals. These results also enhance our understanding of cerebellar functioning by describing the mechanism by which EtOH essentially de‐afferentates (blocks specific inputs to) the cerebellum from the normal processing of sensory signals due to EtOH‐induced Golgi neuron excitation, resulting in inhibition of granule cells. Furthermore, the authors characterize the novel observation of EtOH‐induced neuronal oscillations, which was not previously observed in other preparations.
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