α8‐Integrins are required for hippocampal long‐term potentiation but not for hippocampal‐dependent learning

Integrins are heterodimeric transmembrane cell adhesion receptors that are essential for a wide range of biological functions via cell–matrix and cell–cell interactions. Recent studies have provided evidence that some of the subunits in the integrin family are involved in synaptic and behavioral plasticity. To further understand the role of integrins in the mammalian central nervous system, we generated a postnatal forebrain and excitatory neuron‐specific knockout of α8‐integrin in the mouse. Behavioral studies showed that the mutant mice are normal in multiple hippocampal‐dependent learning tasks, including a T‐maze, non‐match‐to‐place working memory task for which other integrin subunits like α3‐ and β1‐integrin are required. In contrast, mice mutant for α8‐integrin exhibited a specific impairment of long‐term potentiation (LTP) at Schaffer collateral–CA1 synapses, whereas basal synaptic transmission, paired‐pulse facilitation and long‐term depression (LTD) remained unaffected. Because LTP is also impaired in the absence of α3‐integrin, our results indicate that multiple integrin molecules are required for the normal expression of LTP, and different integrins display distinct roles in behavioral and neurophysiological processes like synaptic plasticity.     

Altered synaptic plasticity and behavioral abnormalities in CNGA3‐deficient mice

The role of the cyclic nucleotide‐gated (CNG) channel CNGA3 is well established in cone photoreceptors and guanylyl cyclase‐D‐expressing olfactory neurons. To assess a potential function of CNGA3 in the mouse amygdala and hippocampus, we examined synaptic plasticity and performed a comparative analysis of spatial learning, fear conditioning and step‐down avoidance in wild‐type mice and CNGA3 null mutants (CNGA3^?/?). CNGA3^?/? mice showed normal basal synaptic transmission in the amygdala and the hippocampus. However, cornu Ammonis (CA1) hippocampal long‐term potentiation (LTP) induced by a strong tetanus was significantly enhanced in CNGA3^?/? mice as compared with their wild‐type littermates. Unlike in the hippocampus, LTP was not significantly altered in the amygdala of CNGA3^?/? mice. Enhanced hippocampal LTP did not coincide with changes in hippocampus‐dependent learning, as both wild‐type and mutant mice showed a similar performance in water maze tasks and contextual fear conditioning, except for a trend toward higher step‐down latencies in a passive avoidance task. In contrast, CNGA3^?/? mice showed markedly reduced freezing to the conditioned tone in the amygdala‐dependent cued fear conditioning task. In conclusion, our study adds a new entry on the list of physiological functions of the CNGA3 channel. Despite the dissociation between physiological and behavioral parameters, our data describe a so far unrecognized role of CNGA3 in modulation of hippocampal plasticity and amydgala‐dependent fear memory.     

Wip1 phosphatase modulates both long-term potentiation and long-term depression through the dephosphorylation of CaMKII

Synaptic plasticity is an important mechanism that underlies learning and cognition. Protein phosphorylation by kinases and dephosphorylation by phosphatases play critical roles in the activity-dependent alteration of synaptic plasticity. In this study, we report that Wip1, a protein phosphatase, is essential for long-term potentiation (LTP) and long-term depression (LTD) processes. Wip1-deletion suppresses LTP and enhances LTD in the hippocampus CA1 area. Wip1 deficiency-induced aberrant elevation of CaMKII T286/287 and T305 phosphorylation underlies these dysfunctions. Moreover, we showed that Wip1 modulates CaMKII dephosphorylation. Wip1^?/? mice exhibit abnormal GluR1 membrane expression, which could be reversed by the application of a CaMKII inhibitor, indicating that Wip1/CaMKII signaling is crucial for synaptic plasticity. Together, our results demonstrate that Wip1 phosphatase plays a vital role in regulating hippocampal synaptic plasticity by modulating the phosphorylation of CaMKII.     

Domain Contributions to Signaling Specificity Differences Between Ras-Guanine Nucleotide Releasing Factor (Ras-GRF) 1 and Ras-GRF2

Ras-GRF1 (GRF1) and Ras-GRF2 (GRF2) constitute a family of similar calcium sensors that regulate synaptic plasticity. They are both guanine exchange factors that contain a very similar set of functional domains, including N-terminal pleckstrin homology, coiled-coil, and calmodulin-binding IQ domains and C-terminal Dbl homology Rac-activating domains, Ras-exchange motifs, and CDC25 Ras-activating domains. Nevertheless, they regulate different forms of synaptic plasticity. Although both GRF proteins transduce calcium signals emanating from NMDA-type glutamate receptors in the CA1 region of the hippocampus, GRF1 promotes LTD, whereas GRF2 promotes θ-burst stimulation-induced LTP (TBS-LTP). GRF1 can also mediate high frequency stimulation-induced LTP (HFS-LTP) in mice over 2-months of age, which involves calcium-permeable AMPA-type glutamate receptors. To add to our understanding of how proteins with similar domains can have different functions, WT and various chimeras between GRF1 and GRF2 proteins were tested for their abilities to reconstitute defective LTP and/or LTD in the CA1 hippocampus of Grf1/Grf2 double knock-out mice. These studies revealed a critical role for the GRF2 CDC25 domain in the induction of TBS-LTP by GRF proteins. In contrast, the N-terminal pleckstrin homology and/or coiled-coil domains of GRF1 are key to the induction of HFS-LTP by GRF proteins. Finally, the IQ motif of GRF1 determines whether a GRF protein can induce LTD. Overall, these findings show that for the three forms of synaptic plasticity that are regulated by GRF proteins in the CA1 hippocampus, specificity is encoded in only one or two domains, and a different set of domains for each form of synaptic plasticity.     

Interaction between long-term potentiation and depression in CA1 synapses: temporal constrains, functional compartmentalization and protein synthesis

Information arriving at a neuron via anatomically defined pathways undergoes spatial and temporal encoding. A proposed mechanism by which temporally and spatially segregated information is encoded at the cellular level is based on the interactive properties of synapses located within and across functional dendritic compartments. We examined cooperative and interfering interactions between long-term synaptic potentiation (LTP) and depression (LTD), two forms of synaptic plasticity thought to be key in the encoding of information in the brain. Two approaches were used in CA1 pyramidal neurons of the mouse hippocampus: (1) induction of LTP and LTD in two separate synaptic pathways within the same apical dendritic compartment and across the basal and apical dendritic compartments; (2) induction of LTP and LTD separated by various time intervals (0-90 min). Expression of LTP/LTD interactions was spatially and temporally regulated. While they were largely restricted within the same dendritic compartment (compartmentalized), the nature of the interaction (cooperation or interference) depended on the time interval between inductions. New protein synthesis was found to regulate the expression of the LTP/LTD interference. We speculate that mechanisms for compartmentalization and protein synthesis confer the spatial and temporal modulation by which neurons encode multiplex information in plastic synapses.     

Actin-associated neurabin-protein phosphatase-1 complex regulates hippocampal plasticity

Protein phosphatase-1 (PP1) has been implicated in the control of long-term potentiation (LTP) and depression (LTD) in rat hippocampal CA1 neurons. PP1 catalytic subunits associate with multiple postsynaptic regulatory subunits, but the PP1 complexes that control hippocampal LTP and LTD in the rat hippocampus remain unidentified. The neuron-specific actin-binding protein, neurabin-I, is enriched in dendritic spines, and tethers PP1 to actin-rich postsynaptic density to regulate morphology and maturation of spines. The present studies utilized Sindbis virus-mediated expression of wild-type and mutant neurabin-I polypeptides in organotypic cultures of rat hippocampal slices to investigate their role in synaptic plasticity. While wild-type neurabin-I elicited no change in basal synaptic transmission, it enhanced LTD and inhibited LTP in CA1 pyramidal neurons. By comparison, mutant neurabins, specifically those unable to bind PP1 or F-actin, decreased basal synaptic transmission, attenuated LTD and increased LTP in slice cultures. Biochemical and cell biological analyses suggested that, by mislocalizing synaptic PP1, the mutant neurabins impaired the functions of endogenous neurabin-PP1 complexes and modulated LTP and LTD. Together, these studies provided the first biochemical and physiological evidence that a postsynaptic actin-bound neurabin-I-PP1 complex regulates synaptic transmission and bidirectional changes in hippocampal plasticity.     

The function of GluR1 and GluR2 in cerebellar and hippocampal LTP and LTD is regulated by interplay of phosphorylation and O‐GlcNAc modification

Long‐term potentiation (LTP) and long‐term depression (LTD) are the current models of synaptic plasticity and widely believed to explain how different kinds of memory are stored in different brain regions. Induction of LTP and LTD in different regions of brain undoubtedly involve trafficking of AMPA receptor to and from synapses. Hippocampal LTP involves phosphorylation of GluR1 subunit of AMPA receptor and its delivery to synapse whereas; LTD is the result of dephosphorylation and endocytosis of GluR1 containing AMPA receptor. Conversely the cerebellar LTD is maintained by the phosphorylation of GluR2 which promotes receptor endocytosis while dephosphorylation of GluR2 triggers receptor expression at the cell surface and results in LTP. The interplay of phosphorylation and O‐GlcNAc modification is known as functional switch in many neuronal proteins. In this study it is hypothesized that a same phenomenon underlies as LTD and LTP switching, by predicting the potential of different Ser/Thr residues for phosphorylation, O‐GlcNAc modification and their possible interplay. We suggest the involvement of O‐GlcNAc modification of dephosphorylated GluR1 in maintaining the hippocampal LTD and that of dephosphorylated GluR2 in cerebral LTP. J. Cell. Biochem. 109: 585–597, 2010. © 2010 Wiley‐Liss, Inc.     

Altered cortical synaptic morphology and impaired memory consolidation in forebrain- specific dominant-negative PAK transgenic mice

Molecular and cellular mechanisms for memory consolidation in the cortex are poorly known. To study the relationships between synaptic structure and function in the cortex and consolidation of long-term memory, we have generated transgenic mice in which catalytic activity of PAK, a critical regulator of actin remodeling, is inhibited in the postnatal forebrain. Cortical neurons in these mice displayed fewer dendritic spines and an increased proportion of larger synapses compared to wild-type controls. These alterations in basal synaptic morphology correlated with enhanced mean synaptic strength and impaired bidirectional synaptic modifiability (enhanced LTP and reduced LTD) in the cortex. By contrast, spine morphology and synaptic plasticity were normal in the hippocampus of these mice. Importantly, these mice exhibited specific deficits in the consolidation phase of hippocampus-dependent memory. Thus, our results provide evidence for critical relationships between synaptic morphology and bidirectional modifiability of synaptic strength in the cortex and consolidation of long-term memory.     

AMPA受体与阿尔茨海默病

AMPA受体(α-amino-3-hydroxy-5-methyl-4-isoxa-zolep-propionate receptor,AMPAR)介导中枢神经系统快速兴奋性突触传递,其在突触后膜的动态表达与长时程增强、长时程抑制的诱发和维持有关,参与调节学习记忆活动。AMPAR在β-淀粉样蛋白作用下的过度胞吞和裂解致其在突触后膜缺失,可致突触损伤和功能障碍,与阿尔茨海默病早期认知障碍密切相关。AMPAR还参与谷氨酸介导的兴奋性损伤,Ca2+通透性AMPAR亚型的过度激活能导致阿尔茨海默病神经元的功能障碍甚至死亡。此外,AMPAR还参与tau蛋白的异常磷酸化,与神经原纤维缠结的形成有关。因而突触后膜AMPA受体数目和功能异常可能是导致阿尔兹海默病发生的重要环节。     

Active dendrites,potassium channels and synaptic plasticity

The dendrites of CA1 pyramidal neurons in the hippocampus express numerous types of voltage-gated ion channel, but the distributions or densities of many of these channels are very non-uniform. Sodium channels in the dendrites are responsible for action potential (AP) propagation from the axon into the dendrites (back-propagation); calcium channels are responsible for local changes in dendritic calcium concentrations following back-propagating APs and synaptic potentials; and potassium channels help regulate overall dendritic excitability. Several lines of evidence are presented here to suggest that back-propagating APs, when coincident with excitatory synaptic input, can lead to the induction of either long-term depression (LTD) or long-term potentiation (LTP). The induction of LTD or LTP is correlated with the magnitude of the rise in intracellular calcium. When brief bursts of synaptic potentials are paired with postsynaptic APs in a theta-burst pairing paradigm, the induction of LTP is dependent on the invasion of the AP into the dendritic tree. The amplitude of the AP in the dendrites is dependent, in part, on the activity of a transient, A-type potassium channel that is expressed at high density in the dendrites and correlates with the induction of the LTP. Furthermore, during the expression phase of the LTP, there are local changes in dendritic excitability that may result from modulation of the functioning of this transient potassium channel. The results support the view that the active properties of dendrites play important roles in synaptic integration and synaptic plasticity of these neurons.     

Inflammation Subverts Hippocampal Synaptic Plasticity in Experimental Multiple Sclerosis

Abnormal use-dependent synaptic plasticity is universally accepted as the main physiological correlate of memory deficits in neurodegenerative disorders. It is unclear whether synaptic plasticity deficits take place during neuroinflammatory diseases, such as multiple sclerosis (MS) and its mouse model, experimental autoimmune encephalomyelitis (EAE). In EAE mice, we found significant alterations of synaptic plasticity rules in the hippocampus. When compared to control mice, in fact, hippocampal long-term potentiation (LTP) induction was favored over long-term depression (LTD) in EAE, as shown by a significant rightward shift in the frequency–synaptic response function. Notably, LTP induction was also enhanced in hippocampal slices from control mice following interleukin-1β (IL-1β) perfusion, and both EAE and IL-1β inhibited GABAergic spontaneous inhibitory postsynaptic currents (sIPSC) without affecting glutamatergic transmission and AMPA/NMDA ratio. EAE was also associated with selective loss of GABAergic interneurons and with reduced gamma-frequency oscillations in the CA1 region of the hippocampus. Finally, we provided evidence that microglial activation in the EAE hippocampus was associated with IL-1β expression, and hippocampal slices from control mice incubated with activated microglia displayed alterations of GABAergic transmission similar to those seen in EAE brains, through a mechanism dependent on enhanced IL-1β signaling. These data may yield novel insights into the basis of cognitive deficits in EAE and possibly of MS.     

NMDA Receptor-Dependent Long-Term Potentiation and Long-Term Depression (LTP/LTD)

Long-term potentiation and long-term depression (LTP/LTD) can be elicited by activating N-methyl-d-aspartate (NMDA)-type glutamate receptors, typically by the coincident activity of pre- and postsynaptic neurons. The early phases of expression are mediated by a redistribution of AMPA-type glutamate receptors: More receptors are added to potentiate the synapse or receptors are removed to weaken synapses. With time, structural changes become apparent, which in general require the synthesis of new proteins. The investigation of the molecular and cellular mechanisms underlying these forms of synaptic plasticity has received much attention, because NMDA receptor–dependent LTP and LTD may constitute cellular substrates of learning and memory.Long-term synaptic plasticity is a generic term that applies to a long-lasting experience-dependent change in the efficacy of synaptic transmission. Here we will focus on N-methyl-d-aspartate (NMDA) receptor–dependent synaptic potentiation (LTP) and depression (LTD), two forms of activity-dependent long-term changes in synaptic efficacy that have been extensively studied. Because both LTP and LTD are believed to represent cellular correlates of learning and memory, they have attracted considerable interest. In this article we will focus on the molecular and cellular mechanisms associated with LTP and LTD. As for other forms of long-term synaptic plasticity, a characterization of LTP and LTD involves describing the molecular mechanisms that are required to elicit the change (induction), followed by an investigation of the mechanism of expression (hours) and maintenance (days). The best-characterized form of NMDA receptor (NMDAR)-dependent LTP occurs between CA3 and CA1 pyramidal neurons of the hippocampus (Fig. 1). Throughout the chapter we will mostly refer to this specific form of LTP. At these CA3-CA1 Schaffer collateral synapses, the loci of both induction and expression are situated in the postsynaptic neuron.Open in a separate windowFigure 1.NMDAR-dependent LTD and LTP in the hippocampus. (A) Historical drawing by Ramon y Cajal (1909) of the trisynaptic pathway in the hippocampus. LTP and LTD are induced by activation of NMDARs at synapses between CA3 and CA1 pyramidal neurons (blue and red). In contrast, LTP at mossy fiber synapses onto CA3 neurons (green on blue) is NMDAR-independent. (B) This electron microscopy image shows the densely packed neuropil in the CA1 region of the hippocampus and highlights two asymmetric CA3-CA1 synapses. Note the typical “bouton en passant” configuration of synapse 1 and the prominent spine in synapse 2. The postsynaptic densities (PSDs) are visible. Scale bar, 200 nm. (Image kindly provided by Rafael Luján, Universitad de Castilla-La Mancha.) (C) Bidirectional change in CA3-CA1 synaptic efficacy by LTD and LTP in the same synapses monitored by extracellular field recordings in an acute slice preparation of the hippocampus. Note the contrasting induction protocols (Data from C Lüscher, unpubl.).     

Neurabin contributes to hippocampal long-term potentiation and contextual fear memory

Neurabin is a scaffolding protein that interacts with actin and protein phosphatase-1. Highly enriched in the dendritic spine, neurabin is important for spine morphogenesis and synaptic formation. However, less is known about the role of neurabin in hippocampal plasticity and its possible effect on behavioral functions. Using neurabin knockout (KO) mice, here we studied the function of neurabin in hippocampal synaptic transmission, plasticity and behavioral memory. We demonstrated that neurabin KO mice showed a deficit in contextual fear memory but not auditory fear memory. Whole-cell patch clamp recordings in the hippocampal CA1 neurons showed that long-term potentiation (LTP) was significantly reduced, whereas long-term depression (LTD) was unaltered in neurabin KO mice. Moreover, increased AMPA receptor but not NMDA receptor-mediated synaptic transmission was found in neurabin KO mice, and is accompanied by decreased phosphorylation of GluR1 at the PKA site (Ser845) but no change at the CaMKII/PKC site (Ser831). Pre-conditioning with LTD induction rescued the following LTP in neurabin KO mice, suggesting the loss of LTP may be due to the saturated synaptic transmission. Our results indicate that neurabin regulates contextual fear memory and LTP in hippocampal CA1 pyramidal neurons.     

Glutamatergic plasticity by synaptic delivery of GluR-B(long)-containing AMPA receptors

Activity-driven delivery of AMPA receptors is proposed to mediate glutamatergic synaptic plasticity, both during development and learning. In hippocampal CA1 principal neurons, such trafficking is primarily mediated by the abundant GluR-A subunit. We now report a study of GluR-B(long), a C-terminal splice variant of the GluR-B subunit. GluR-B(long) synaptic delivery is regulated by two forms of activity. Spontaneous synaptic activity-driven GluR-B(long) transport maintains one-third of the steady-state AMPA receptor-mediated responses, while GluR-B(long) delivery following the induction of LTP is responsible for approximately 50% of the resulting potentiation at the hippocampal CA3 to CA1 synapses at the time of GluR-B(long) peak expression-the second postnatal week. Trafficking of GluR-B(long)-containing receptors thus mediates a GluR-A-independent form of glutamatergic synaptic plasticity in the juvenile hippocampus.     

PTEN is recruited to the postsynaptic terminal for NMDA receptor‐dependent long‐term depression

Phosphatase and tensin homolog deleted on chromosome ten (PTEN) is an important regulator of phosphatidylinositol‐(3,4,5,)‐trisphosphate signalling, which controls cell growth and differentiation. However, PTEN is also highly expressed in the adult brain, in which it can be found in dendritic spines in hippocampus and other brain regions. Here, we have investigated specific functions of PTEN in the regulation of synaptic function in excitatory hippocampal synapses. We found that NMDA receptor activation triggers a PDZ‐dependent association between PTEN and the synaptic scaffolding molecule PSD‐95. This association is accompanied by PTEN localization at the postsynaptic density and anchoring within the spine. On the other hand, enhancement of PTEN lipid phosphatase activity is able to drive depression of AMPA receptor‐mediated synaptic responses. This activity is specifically required for NMDA receptor‐dependent long‐term depression (LTD), but not for LTP or metabotropic glutamate receptor‐dependent LTD. Therefore, these results reveal PTEN as a regulated signalling molecule at the synapse, which is recruited to the postsynaptic membrane upon NMDA receptor activation, and is required for the modulation of synaptic activity during plasticity.     

Impaired hippocampal long-term potentiation and failure of learning in β1,4-N-acetylgalactosaminyltransferase gene transgenic mice

Gangliosides (sialic acid-containing glycosphingolipids) play important roles in many physiological functions, including synaptic plasticity in the hippocampus, which is considered as a cellular mechanism of learning and memory. In the present study, three types of synaptic plasticity, long-term potentiation (LTP), long-term depression (LTD) and reversal of LTP (depotentiation, DP), in the field excitatory post-synaptic potential in CA1 hippocampal neurons and learning behavior were examined in β1,4-N-acetylgalactosaminyltransferase (β1,4 GalNAc-T; GM2/GD2 synthase) gene transgenic (TG) mice, which showed a marked decrease in b-pathway gangliosides (GQ1b, GT1b and GD1b) in the brain and isolated hippocampus compared with wild-type (WT) mice. The magnitude of the LTP induced by tetanus (100 pulses at 100?Hz) in TG mice was significantly smaller than that in control WT mice, whereas there was no difference in the magnitude of the LTD induced by three short trains of low-frequency stimulation (LFS) (200 pulses at 1?Hz) at 20?min intervals between the two groups of mice. The reduction in the LTP produced by delivering three trains of LFS (200 pulses at 1?Hz, 20?min intervals) was significantly greater in the TG mice than in the WT mice. Learning was impaired in the four-pellet taking test (4PTT) in TG mice, with no significant difference in daily activity or activity during the 4PTT between TG and WT mice. These results suggest that the overexpression of β1,4 GalNAc-T resulted in altered synaptic plasticity of LTP and DP in hippocampal CA1 neurons and learning in the 4PTT, and this is attributable to the shift from b-pathway gangliosides to a-pathway gangliosides.     

Local learning rules: predicted influence of dendritic location on synaptic modification in spike-timing-dependent plasticity

Recent indirect experimental evidence suggests that synaptic plasticity changes along the dendrites of a neuron. Here we present a synaptic plasticity rule which is controlled by the properties of the pre- and postsynaptic signals. Using recorded membrane traces of back-propagating and dendritic spikes we demonstrate that LTP and LTD will depend specifically on the shape of the postsynaptic depolarization at a given dendritic site. We find that asymmetrical spike-timing-dependent plasticity (STDP) can be replaced by temporally symmetrical plasticity within physiologically relevant time windows if the postsynaptic depolarization rises shallow. Presynaptically the rule depends on the NMDA channel characteristic, and the model predicts that an increase in Mg²⁺ will attenuate the STDP curve without changing its shape. Furthermore, the model suggests that the profile of LTD should be governed by the postsynaptic signal while that of LTP mainly depends on the presynaptic signal shape.     

Learning,AMPA receptor mobility and synaptic plasticity depend on n‐cofilin‐mediated actin dynamics

Neuronal plasticity is an important process for learning, memory and complex behaviour. Rapid remodelling of the actin cytoskeleton in the postsynaptic compartment is thought to have an important function for synaptic plasticity. However, the actin‐binding proteins involved and the molecular mechanisms that in vivo link actin dynamics to postsynaptic physiology are not well understood. Here, we show that the actin filament depolymerizing protein n‐cofilin is controlling dendritic spine morphology and postsynaptic parameters such as late long‐term potentiation and long‐term depression. Loss of n‐cofilin‐mediated synaptic actin dynamics in the forebrain specifically leads to impairment of all types of associative learning, whereas exploratory learning is not affected. We provide evidence for a novel function of n‐cofilin function in synaptic plasticity and in the control of extrasynaptic excitatory AMPA receptors diffusion. These results suggest a critical function of actin dynamics in associative learning and postsynaptic receptor availability.     

β-adducin (Add2) KO mice show synaptic plasticity, motor coordination and behavioral deficits accompanied by changes in the expression and phosphorylation levels of the α- and γ-adducin subunits

Adducins are a family of proteins found in cytoskeleton junctional complexes, which bind and regulate actin filaments and actin-spectrin complexes. In brain, adducin is expressed at high levels and is identified as a constituent of synaptic structures, such as dendritic spines and growth cones of neurons. Adducin-induced changes in dendritic spines are involved in activity-dependent synaptic plasticity processes associated with learning and memory, but the mechanisms underlying these functions remain to be elucidated. Here, β-adducin knockout (KO) mice were used to obtain a deeper insight into the role of adducin in these processes. We showed that β-adducin KO mice showed behavioral, motor coordination and learning deficits together with an altered expression and/or phosphorylation levels of α-adducin and γ-adducin. We found that β-adducin KO mice exhibited deficits in learning and motor performances associated with an impairment of long-term potentiation (LTP) and long-term depression (LTD) in the hippocampus. These effects were accompanied by a decrease in phosphorylation of adducin, a reduction in α-adducin expression levels and upregulation of γ-adducin in hippocampus, cerebellum and neocortex of mutant mice. In addition, we found that the mRNA encoding β-adducin is also located in dendrites, where it may participate in the fine modulation of LTP and LTD. These results strongly suggest coordinated expression and phosphorylation of adducin subunits as a key mechanism underlying synaptic plasticity, motor coordination performance and learning behaviors.     

Endocannabinoids Differentially Modulate Synaptic Plasticity in Rat Hippocampal CA1 Pyramidal Neurons

Background

Hippocampal CA1 pyramidal neurons receive two excitatory glutamatergic synaptic inputs: their most distal dendritic regions in the stratum lacunosum-moleculare (SLM) are innervated by the perforant path (PP), originating from layer III of the entorhinal cortex, while their more proximal regions of the apical dendrites in the stratum radiatum (SR) are innervated by the Schaffer-collaterals (SC), originating from hippocampal CA3 neurons. Endocannabinoids (eCBs) are naturally occurring mediators capable of modulating both GABAergic and glutamatergic synaptic transmission and plasticity via the CB1 receptor. Previous work on eCB modulation of excitatory synapses in the CA1 region largely focuses on the SC pathway. However, little information is available on whether and how eCBs modulate glutamatergic synaptic transmission and plasticity at PP synapses.

Methodology/Principal Findings

By employing somatic and dendritic patch-clamp recordings, Ca²⁺ uncaging, and immunostaining, we demonstrate that there are significant differences in low-frequency stimulation (LFS)- or DHPG-, an agonist of group I metabotropic glutamate receptors (mGluRs), induced long-term depression (LTD) of excitatory synaptic transmission between SC and PP synapses in the same pyramidal neurons. These differences are eliminated by pharmacological inhibition with selective CB1 receptor antagonists or genetic deletion of the CB1 receptor, indicating that these differences likely result from differential modulation via a CB1 receptor-dependent mechanism. We also revealed that depolarization-induced suppression of excitation (DSE), a form of short-term synaptic plasticity, and photolysis of caged Ca²⁺-induced suppression of Excitatory postsynaptic currents (EPSCs) were less at the PP than that at the SC. In addition, application of WIN55212 (WIN) induced a more pronounced inhibition of EPSCs at the SC when compared to that at the PP.

Conclusions/Significance

Our results suggest that CB1 dependent LTD and DSE are differentially expressed at the PP versus SC synapses in the same neurons, which may have an impact on synaptic scaling, integration and plasticity of hippocampal CA1 pyramidal neurons.