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Open Access Publications from the University of California

Scholarly Works (16 results)

  • Article
  • Peer Reviewed
UCLA Previously Published Works (2022)
Although Hebbian LTP has an important role in memory formation, the properties of Hebbian LTP cannot fully account for, and in some cases seem incompatible with, fundamental properties of associative learning. Importantly, findings from computational and neurophysiological studies suggest that burst-dependent forms of plasticity, where dendritic spikes and bursts of action potentials provide the postsynaptic depolarization needed for LTP induction, may overcome some of the limitations of conventional Hebbian LTP. Thus, I investigated how excitatory synapses onto CA1 pyramidal cells interact during the induction of complex spike (CS) burst-dependent LTP in hippocampal slices from male mice. Consistent with previous findings, theta-frequency trains of synaptic stimulation induce a Hebbian form of plasticity where postsynaptic CS bursts provide the depolarization needed for NMDAR activation and LTP induction. However, in contrast to conventional Hebbian plasticity, where cooperative LTP induction requires coactivation of synapses on a timescale of tens of milliseconds, cooperative interactions between synapses activated several seconds apart can induce CS burst-dependent LTP. A novel, retroactive form of heterosynaptic plasticity, where activation of one group of synapses triggers LTP induction at other synapses that were active seconds earlier, also contributes to cooperativity in CS burst-dependent LTP. Moreover, competitive synaptic interactions that emerge during prolonged bouts of postsynaptic CS bursting potently regulate CS burst-dependent LTP. Together, the unusual properties of synaptic cooperativity and competition in CS burst-dependent LTP enable Hebbian synapses to operate and interact on behavioral timescales.SIGNIFICANCE STATEMENT While EPSP-evoked complex spike (CS) bursting induces LTP at excitatory synapses onto hippocampal CA1 pyramidal cells, the properties of synaptic interactions during the induction of CS burst-dependent LTP have not been investigated. Here I report that interactions between independent synaptic inputs during the induction of CS burst-dependent LTP exhibit a number of novel, computationally relevant properties. Unlike conventional Hebbian LTP, the induction of CS burst-dependent LTP is regulated by proactive and retroactive cooperative interactions between synapses activated several seconds apart. Moreover, activity-dependent, competitive interactions between synapses allow strongly activated synapses to suppress LTP induction at more weakly activated synapses. Thus, CS burst-dependent LTP exhibits a number of the unique properties that overcome significant limitations of standard Hebbian plasticity rules.
    Cover page: Behavioral Timescale Cooperativity and Competitive Synaptic Interactions Regulate the Induction of Complex Spike Burst-Dependent Long-Term Potentiation.
    • Thesis
    • Peer Reviewed
    UCLA Electronic Theses and Dissertations (2016)

    Synaptic plasticity is an essential mechanism for both the creation of memories and the

    formation of associations between those memories. A crucial component of learning and

    memory is the hippocampus. The works included in this thesis probe the cellular basis of

    learning and memory in the hippocampus through two primary means. The first builds upon

    existing information highlighting the stark difference in plasticity between the dorsal and ventral poles of the hippocampus along with the preferential influence of neuromodulators

    on ventral plasticity. The second examines the importance of phosphorylation-based regulation of the AMPA receptor subunit, GluA1, and how this mediates hippocampal plasticity.

    Despite similar basal excitatory and inhibitory synaptic transmission between the two

    poles, the ventral hippocampus exhibits much weaker long term potentiation (LTP) and complex spiking compared to the dorsal. This deficit was due to a down regulation of the NMDA receptors in the ventral region, which resulted in weaker E-S coupling and EPSP amplification. LTP induction and complex spiking, however, could be rescued with the addition of a β-adrenergic agonist. Additionally, β-adrenergic activation inhibited the small conductance calcium-activated potassium channel, SK, which serves to hyperpolarize the cell and resist NMDA receptor activation. Indeed, pharmacological inhibition of the SK channel enhanced LTP induction, complex spiking, E-S coupling, and EPSP amplification in the ventral hippocampus.

    The second part of this thesis examined the role of two particular GluA1 phosphorylation

    sites, S845 and T840, and how their phosphorylation states affect hippocampal plasticity. We

    found that S845 and T840 are regulated by distinct calcium sources and phosphatases and also track synaptic strength in different ways. S845 is persistently dephosphorylated following either depolarization or LTD induction, whereas T840 only remains dephosphorylated after LTD induction. Furthermore, we found inhibitory phospho-site interactions between the two sites, due to their close proximity to one another. We then determined the basal phosphorylation levels of both sites and discovered that S845 phosphorylation levels were so low we could not adequately quantify them while T840 residues were phosphorylated in approximately ~50% of GluA1 subunits.

    This thesis has served two important roles in the elucidation of plasticity in the

    hippocampus, as it has i) identified a potent role of noradrenergic signaling in facilitating LTP

    induction in the ventral hippocampus and ii) detailed the regulation and prevalence of T840 and S845 in the hippocampus, along with their involvement in plasticity.

      Cover page: Cellular and molecular studies on hippocampal plasticity: region-dependent effects of β-adrenergic signaling and the regulation of AMPA receptor phosphorylation
      • Thesis
      • Peer Reviewed
      UCLA Electronic Theses and Dissertations (2018)

      Behavioral, physiological, and anatomical evidence indicates that the dorsal and ventral zones of the hippocampus have distinct roles in cognition. How the unique functions of these zones might depend on differences in synaptic and neuronal function arising from the strikingly different gene expression profiles exhibited by dorsal and ventral CA1 pyramidal cells is unclear. To begin to address this question, I investigated the mechanisms underlying differences in synaptic transmission and plasticity at dorsal and ventral Schaffer collateral (SC) synapses.

      Strikingly, although basal synaptic transmission is similar, SC synapses in the dorsal and ventral hippocampus exhibit markedly different responses to theta-frequency patterns of stimulation. In contrast to dorsal hippocampus, theta-frequency stimulation fails to elicit postsynaptic complex-spike bursting and does not induce LTP at ventral SC synapses. Moreover, EPSP-spike coupling, a process that strongly influences information transfer at synapses, is weaker in ventral pyramidal cells. All of these differences in postsynaptic function are due to an enhanced activation of SK-type K+ channels that suppresses NMDA receptor (NMDAR)-dependent EPSP amplification at ventral SC synapses. Consistent with this, mRNA levels for the SK3 subunit of SK channels are significantly higher in ventral CA1 pyramidal cells. Together, my findings indicated that a dorsal-ventral difference in SK channel regulation of NMDAR activation has a profound effect on the transmission, processing and storage of information at SC synapses and thus likely contributes to the distinct roles of the dorsal and ventral hippocampus in different behaviors. SK channel activity at dendritic spines is strongly down-regulated by -adrenergic (Carter et al. 2012) and muscarinic receptor activation (Buchanan et al. 2010; Giessel and Sabatini 2010). Thus, in addition to coincident pre- and postsynaptic activity, the induction of LTP at SC synapses in the ventral hippocampus may be highly state-dependent and require the release of modulatory neurotransmitters, such as norepinephrine or acetylcholine, to overcome the SK channel inhibition of NMDAR activation. Experiments in this dissertation focus on muscarinic neuromodulation of dorsal and ventral hippocampus and its effect on pyramidal cell excitability and LTP across dorsal-ventral axis of mouse hippocampus.

        Cover page: Muscarinic Modulation of Pyramidal Cell Excitability and Long Term Potentiation Across Dorsal-Ventral Axis of Mouse Hippocampus
        • Article
        • Peer Reviewed
        UCLA Previously Published Works (2016)
        Dephosphorylation of AMPA receptor (AMPAR) GluA1 subunits at two sites, serine 845 (S845) and threonine 840 (T840), is thought to be involved in NMDA receptor-dependent forms of long-term depression (LTD). Importantly, the notion that dephosphorylation of these sites contributes to LTD assumes that a significant fraction of GluA1 subunits are basally phosphorylated at these sites. To examine this question, we used immunoprecipitation/depletion assays to estimate the proportion of GluA1 subunits basally phosphorylated at S845 and T840. Although dephosphorylation of S845 is thought to have a key role in LTD, our results indicate that few GluA1 subunits in hippocampal neurons are phosphorylated at this site. In contrast, ∼50% of GluA1 subunits are basally phosphorylated at T840, suggesting that dephosphorylation of this site can contribute to the down-regulation of AMPAR-mediated synaptic transmission in LTD.
          Cover page: Basal levels of AMPA receptor GluA1 subunit phosphorylation at threonine 840 and serine 845 in hippocampal neurons
          • Article
          • Peer Reviewed
          UCLA Previously Published Works (2012)
          Postsynaptic density protein 95 (PSD-95) is essential for synaptic maturation and plasticity. Although its synaptic regulation has been widely studied, the control of PSD-95 cellular expression is not understood. We found that Psd-95 was controlled post-transcriptionally during neural development. Psd-95 was transcribed early in mouse embryonic brain, but most of its product transcripts were degraded. The polypyrimidine tract binding proteins PTBP1 and PTBP2 repressed Psd-95 (also known as Dlg4) exon 18 splicing, leading to premature translation termination and nonsense-mediated mRNA decay. The loss of first PTBP1 and then of PTBP2 during embryonic development allowed splicing of exon 18 and expression of PSD-95 late in neuronal maturation. Re-expression of PTBP1 or PTBP2 in differentiated neurons inhibited PSD-95 expression and impaired the development of glutamatergic synapses. Thus, expression of PSD-95 during early neural development is controlled at the RNA level by two PTB proteins whose sequential downregulation is necessary for synapse maturation.
            Cover page: PSD-95 is post-transcriptionally repressed during early neural development by PTBP1 and PTBP2
            • Article
            • Peer Reviewed
            UCLA Previously Published Works (2014)
            The C terminus of AMPA-type glutamate receptor (AMPAR) GluA1 subunits contains several phosphorylation sites that regulate AMPAR activity and trafficking at excitatory synapses. Although many of these sites have been extensively studied, little is known about the signaling mechanisms regulating GluA1 phosphorylation at Thr-840. Here, we report that neuronal depolarization in hippocampal slices induces a calcium and protein phosphatase 1/2A-dependent dephosphorylation of GluA1 at Thr-840 and a nearby site at Ser-845. Despite these similarities, inhibitors of NMDA-type glutamate receptors and protein phosphatase 2B prevented depolarization-induced Ser-845 dephosphorylation but had no effect on Thr-840 dephosphorylation. Instead, depolarization-induced Thr-840 dephosphorylation was prevented by blocking voltage-gated calcium channels, indicating that distinct Ca(2+) sources converge to regulate GluA1 dephosphorylation at Thr-840 and Ser-845 in separable ways. Results from immunoprecipitation/depletion assays indicate that Thr-840 phosphorylation inhibits protein kinase A (PKA)-mediated increases in Ser-845 phosphorylation. Consistent with this, PKA-mediated increases in AMPAR currents, which are dependent on Ser-845 phosphorylation, were inhibited in HEK-293 cells expressing a Thr-840 phosphomimetic version of GluA1. Conversely, mimicking Ser-845 phosphorylation inhibited protein kinase C phosphorylation of Thr-840 in vitro, and PKA activation inhibited Thr-840 phosphorylation in hippocampal slices. Together, the regulation of Thr-840 and Ser-845 phosphorylation by distinct sources of Ca(2+) influx and the presence of inhibitory interactions between these sites highlight a novel mechanism for conditional regulation of AMPAR phosphorylation and function.
              Cover page: Inhibitory Interactions between Phosphorylation Sites in the C Terminus of α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid-type Glutamate Receptor GluA1 Subunits*
              • Article
              • Peer Reviewed
              UCLA Previously Published Works (2017)
              Behavioral, physiological, and anatomical evidence indicates that the dorsal and ventral zones of the hippocampus have distinct roles in cognition. How the unique functions of these zones might depend on differences in synaptic and neuronal function arising from the strikingly different gene expression profiles exhibited by dorsal and ventral CA1 pyramidal cells is unclear. To begin to address this question, we investigated the mechanisms underlying differences in synaptic transmission and plasticity at dorsal and ventral Schaffer collateral (SC) synapses in the mouse hippocampus. We find that, although basal synaptic transmission is similar, SC synapses in the dorsal and ventral hippocampus exhibit markedly different responses to θ frequency patterns of stimulation. In contrast to dorsal hippocampus, θ frequency stimulation fails to elicit postsynaptic complex-spike bursting and does not induce LTP at ventral SC synapses. Moreover, EPSP-spike coupling, a process that strongly influences information transfer at synapses, is weaker in ventral pyramidal cells. Our results indicate that all these differences in postsynaptic function are due to an enhanced activation of SK-type K+ channels that suppresses NMDAR-dependent EPSP amplification at ventral SC synapses. Consistent with this, mRNA levels for the SK3 subunit of SK channels are significantly higher in ventral CA1 pyramidal cells. Together, our findings indicate that a dorsal-ventral difference in SK channel regulation of NMDAR activation has a profound effect on the transmission, processing, and storage of information at SC synapses and thus likely contributes to the distinct roles of the dorsal and ventral hippocampus in different behaviors.SIGNIFICANCE STATEMENT Differences in short- and long-term plasticity at Schaffer collateral (SC) synapses in the dorsal and ventral hippocampus likely contribute importantly to the distinct roles of these regions in cognition and behavior. Although dorsal and ventral CA1 pyramidal cells exhibit markedly different gene expression profiles, how these differences influence plasticity at SC synapses is unclear. Here we report that increased mRNA levels for the SK3 subunit of SK-type K+ channels in ventral pyramidal cells is associated with an enhanced activation of SK channels that strongly suppresses NMDAR activation at ventral SC synapses. This leads to striking differences in multiple aspects of synaptic transmission at dorsal and ventral SC synapses and underlies the reduced ability of ventral SC synapses to undergo LTP.
                Cover page: Differential Regulation of NMDA Receptor-Mediated Transmission by SK Channels Underlies Dorsal-Ventral Differences in Dynamics of Schaffer Collateral Synaptic Function
                • Article
                • Peer Reviewed
                UCLA Previously Published Works (2018)
                Cognitive impairment (CI), a debilitating and pervasive feature of multiple sclerosis (MS), is correlated with hippocampal atrophy. Findings from postmortem MS hippocampi indicate that expression of genes involved in both excitatory and inhibitory neurotransmission are altered in MS, and although deficits in excitatory neurotransmission have been reported in the MS model experimental autoimmune encephalomyelitis (EAE), the functional consequence of altered inhibitory neurotransmission remains poorly understood. In this study, we used electrophysiological and biochemical techniques to examine inhibitory neurotransmission in the CA1 region of the hippocampus in EAE. We find that tonic, GABAergic inhibition is enhanced in CA1 pyramidal cells from EAE mice. Although plasma membrane expression of the GABA transporter GAT-3 was decreased in the EAE hippocampus, an increased surface expression of α5 subunit-containing GABAA receptors appears to be primarily responsible for the increase in tonic inhibition during EAE. Enhanced tonic inhibition during EAE was associated with decreased CA1 pyramidal cell excitability and inhibition of α5 subunit-containing GABAA receptors with the negative allosteric modulator L-655,708 enhanced pyramidal cell excitability in EAE mice. Together, our results suggest that altered GABAergic neurotransmission may underlie deficits in hippocampus-dependent cognitive function in EAE and MS.
                  Cover page: Enhanced GABAergic Tonic Inhibition Reduces Intrinsic Excitability of Hippocampal CA1 Pyramidal Cells in Experimental Autoimmune Encephalomyelitis
                  • Article
                  • Peer Reviewed
                  UCLA Previously Published Works (2020)
                  The ACC is implicated in effort exertion and choices based on effort cost, but it is still unclear how it mediates this cost-benefit evaluation. Here, male rats were trained to exert effort for a high-value reward (sucrose pellets) in a progressive ratio lever-pressing task. Trained rats were then tested in two conditions: a no-choice condition where lever-pressing for sucrose was the only available food option, and a choice condition where a low-value reward (lab chow) was freely available as an alternative to pressing for sucrose. Disruption of ACC, via either chemogenetic inhibition or excitation, reduced lever-pressing in the choice, but not in the no-choice, condition. We next looked for value coding cells in ACC during effortful behavior and reward consumption phases during choice and no-choice conditions. For this, we used in vivo miniaturized fluorescence microscopy to reliably track responses of the same cells and compare how ACC neurons respond during the same effortful behavior where there was a choice versus when there was no-choice. We found that lever-press and sucrose-evoked responses were significantly weaker during choice compared with no-choice sessions, which may have rendered them more susceptible to chemogenetic disruption. Together, findings from our interference experiments and neural recordings suggest that a mechanism by which ACC mediates effortful decisions is in the discrimination of the utility of available options. ACC regulates these choices by providing a stable population code for the relative value of different options.SIGNIFICANCE STATEMENT The ACC is implicated in effort-based decision-making. Here, we used chemogenetics and in vivo calcium imaging to explore its mechanism. Rats were trained to lever press for a high-value reward and tested in two conditions: a no-choice condition where lever-pressing for the high-value reward was the only option, and a choice condition where a low-value reward was also available. Inhibition or excitation of ACC reduced effort toward the high-value option, but only in the choice condition. Neural responses in ACC were weaker in the choice compared with the no-choice condition. A mechanism by which ACC regulates effortful decisions is in providing a stable population code for the discrimination of the utility of available options.
                    Cover page: Chemogenetic modulation and single-photon calcium imaging in anterior cingulate cortex reveal a mechanism for effort-based decisions
                    • Article
                    • Peer Reviewed
                    UCLA Previously Published Works (2015)
                    Robust sleep/wake rhythms are important for health and cognitive function. Unfortunately, many people are living in an environment where their circadian system is challenged by inappropriate meal- or work-times. Here we scheduled food access to the sleep time and examined the impact on learning and memory in mice. Under these conditions, we demonstrate that the molecular clock in the master pacemaker, the suprachiasmatic nucleus (SCN), is unaltered while the molecular clock in the hippocampus is synchronized by the timing of food availability. This chronic circadian misalignment causes reduced hippocampal long term potentiation and total CREB expression. Importantly this mis-timed feeding resulted in dramatic deficits in hippocampal-dependent learning and memory. Our findings suggest that the timing of meals have far-reaching effects on hippocampal physiology and learned behaviour.
                      Cover page: Misaligned feeding impairs memoriesCreative Commons 'BY-NC' version 4.0 license
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