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1.  Neuronal Cx3cr1 Deficiency Protects against Amyloid β-Induced Neurotoxicity 
PLoS ONE  2015;10(6):e0127730.
Cx3cr1, the receptor for the chemokine Cx3cl1 (fractalkine), has been implicated in the progression and severity of Alzheimer’s disease-like pathology in mice, but the underlying mechanisms remain unclear. A complicating factor is that Cx3cr1 has been demonstrated in both neurons and microglia. Here, we have dissected the differences between neuronal and microglial Cx3cr1, specifically by comparing direct amyloid-β-induced toxicity in cultured, mature, microglia-depleted hippocampal neurons from wild-type and Cx3cr1-/- mice. Wild-type neurons expressed both Cx3cl1 and Cx3cr1 and released Cx3cl1 in response to amyloid-β. Knockout of neuronal Cx3cr1 abated amyloid-β-induced lactate dehydrogenase release. Furthermore, amyloid-β differentially induced depression of pre- and postsynaptic components of miniature excitatory postsynaptic currents, in a peptide conformation-dependent manner. Knockout of neuronal Cx3cr1 abated effects of both amyloid-β conformational states, which were differentiable by aggregation kinetics and peptide morphology. We obtained similar results after both acute and chronic treatment of cultured neurons with the Cx3cr1 antagonist F1. Thus, neuronal Cx3cr1 may impact Alzheimer’s disease-like pathology by modulating conformational state-dependent amyloid-β-induced synaptotoxicity.
PMCID: PMC4454597  PMID: 26038823
2.  Emergence of Rich-Club Topology and Coordinated Dynamics in Development of Hippocampal Functional Networks In Vitro 
The Journal of Neuroscience  2015;35(14):5459-5470.
Recent studies demonstrated that the anatomical network of the human brain shows a “rich-club” organization. This complex topological feature implies that highly connected regions, hubs of the large-scale brain network, are more densely interconnected with each other than expected by chance. Rich-club nodes were traversed by a majority of short paths between peripheral regions, underlining their potential importance for efficient global exchange of information between functionally specialized areas of the brain. Network hubs have also been described at the microscale of brain connectivity (so-called “hub neurons”). Their role in shaping synchronous dynamics and forming microcircuit wiring during development, however, is not yet fully understood. The present study aimed to investigate the role of hubs during network development, using multi-electrode arrays and functional connectivity analysis during spontaneous multi-unit activity (MUA) of dissociated primary mouse hippocampal neurons. Over the first 4 weeks in vitro, functional connectivity significantly increased in strength, density, and size, with mature networks demonstrating a robust modular and small-world topology. As expected by a “rich-get-richer” growth rule of network evolution, MUA graphs were found to form rich-clubs at an early stage in development (14 DIV). Later on, rich-club nodes were a consistent topological feature of MUA graphs, demonstrating high nodal strength, efficiency, and centrality. Rich-club nodes were also found to be crucial for MUA dynamics. They often served as broker of spontaneous activity flow, confirming that hub nodes and rich-clubs may play an important role in coordinating functional dynamics at the microcircuit level.
PMCID: PMC4388914  PMID: 25855164
development; electrophysiology; hippocampus; hubs; network
3.  Distinct roles of GABAA and GABAB receptors in balancing and terminating persistent cortical activity 
Cortical networks spontaneously fluctuate between persistently active UP states and quiescent DOWN states. The UP states are maintained by recurrent excitation within local circuits, and can be turned on and off by synaptic input. GABAergic inhibition is believed to be important for stabilizing such persistent activity by balancing the excitation, and could have an additional role in terminating the UP state. Here we report that GABAA and GABAB receptor-mediated inhibition have distinct and complementary roles in balancing and terminating persistent activity. In a model of UP-DOWN states expressed in slices of rat entorhinal cortex, the GABAA receptor antagonist, gabazine (50-500 nM), concentration-dependently decreased UP state duration, eventually leading to epileptiform bursts. In contrast, the GABAB receptor antagonist, CGP55845 (50 nM – 1 μM), increased the duration of persistent network activity, and prevented stimulus-induced DOWN state transitions. These results suggest that while GABAA receptor-mediated inhibition is necessary for balancing persistent activity, activation of GABAB receptors contributes to terminating UP states.
PMCID: PMC4326656  PMID: 19515919
GABA; inhibition; network; persistent activity; UP/DOWN states; entorhinal cortex
4.  Preynaptic induction and expression of t-LTD demonstrated by compartment-specific photorelease of a use-dependent NMDA receptor antagonist 
N-methyl-d-aspartate (NMDA) receptors are important for synaptic plasticity, including long-term potentiation (LTP) and long-term depression (LTD). In order to help investigate the precise location of the NMDA receptors that are required for different types of synaptic plasticity, we synthesized a caged form of the use-dependent NMDA receptor antagonist, MK801, which we loaded into individual neurons in vitro, followed by compartment-specific uncaging. To demonstrate the potential of this new method, we investigated timing-dependent plasticity at layer 4-layer 2/3 synapses of mouse barrel cortex. Somatodendritic photorelease of MK801 in the postsynaptic neuron produced a use-dependent block of synaptic NMDA receptor-mediated currents and prevented the induction of LTP. Compartment-specific photorelease of MK801 in the presynaptic neuron showed that axonal, but not somatodendritic, presynaptic NMDA receptors are required for induction of LTD. The rate of use-dependent block of postsynaptic NMDA receptor current was slower following induction of LTD, consistent with a presynaptic locus of expression. Thus, this new caged compound has demonstrated the axonal location of NMDA receptors required for induction and the presynaptic locus of expression of LTD at layer 4-layer 2/3 synapses.
PMCID: PMC4299820  PMID: 21653860
Mouse; barrel cortex; LTD; NMDA; MK801; photolysis
5.  Oscillatory Activity in the Medial Prefrontal Cortex and Nucleus Accumbens Correlates with Impulsivity and Reward Outcome 
PLoS ONE  2014;9(10):e111300.
Actions expressed prematurely without regard for their consequences are considered impulsive. Such behaviour is governed by a network of brain regions including the prefrontal cortex (PFC) and nucleus accumbens (NAcb) and is prevalent in disorders including attention deficit hyperactivity disorder (ADHD) and drug addiction. However, little is known of the relationship between neural activity in these regions and specific forms of impulsive behaviour. In the present study we investigated local field potential (LFP) oscillations in distinct sub-regions of the PFC and NAcb on a 5-choice serial reaction time task (5-CSRTT), which measures sustained, spatially-divided visual attention and action restraint. The main findings show that power in gamma frequency (50–60 Hz) LFP oscillations transiently increases in the PFC and NAcb during both the anticipation of a cue signalling the spatial location of a nose-poke response and again following correct responses. Gamma oscillations were coupled to low-frequency delta oscillations in both regions; this coupling strengthened specifically when an error response was made. Theta (7–9 Hz) LFP power in the PFC and NAcb increased during the waiting period and was also related to response outcome. Additionally, both gamma and theta power were significantly affected by upcoming premature responses as rats waited for the visual cue to respond. In a subgroup of rats showing persistently high levels of impulsivity we found that impulsivity was associated with increased error signals following a nose-poke response, as well as reduced signals of previous trial outcome during the waiting period. Collectively, these in-vivo neurophysiological findings further implicate the PFC and NAcb in anticipatory impulsive responses and provide evidence that abnormalities in the encoding of rewarding outcomes may underlie trait-like impulsive behaviour.
PMCID: PMC4205097  PMID: 25333512
6.  Dopamine suppresses persistent network activity via D1-like dopamine receptors in rat medial entorhinal cortex 
The European journal of neuroscience  2013;37(8):1242-1247.
Cortical networks display persistent activity in the form of periods of sustained synchronous depolarisations (‘UP states’) punctuated by periods of relative hyperpolarisation (‘DOWN states’), which together form the slow oscillation. UP states are known to be synaptically generated and are sustained by a dynamic balance of excitation and inhibition, with fast ionotropic glutamatergic excitatory and GABAergic inhibitory conductances increasing during the UP state. Previously, work from our group demonstrated that slow metabotropic GABA receptors also play an important role in terminating the UP state, but the effects of other neuromodulators on this network phenomenon received little attention. Given that persistent activity is a neural correlate of working memory and that signalling through dopamine receptors has been shown to be critical for working memory tasks, we examined whether dopaminergic neurotransmission affected the slow oscillation. Here, using an in vitro model of the slow oscillation in rat medial entorhinal cortex, we show that dopamine strongly and reversibly suppresses cortical UP states. We show that this effect is mediated through D1-like and not D2-like dopamine receptors, and we found no evidence that tonic dopaminergic transmission affected UP states in our model.
PMCID: PMC3628042  PMID: 23336973
slow oscillation; UP states; cortex
7.  Distinct mechanisms of spike timing‐dependent LTD at vertical and horizontal inputs onto L2/3 pyramidal neurons in mouse barrel cortex 
Physiological Reports  2014;2(3):e00271.
Spike timing‐dependent plasticity (STDP) is an attractive candidate to mediate the synaptic changes that support circuit plasticity in sensory cortices during development. STDP is prevalent at excitatory synapses, but it is not known whether the underlying mechanisms are universal, or whether distinct mechanisms underpin STDP at different synapses. Here, we set out to compare and contrast STDP at vertical layer 4 and horizontal layer 2/3 inputs onto postsynaptic layer 2/3 neurons in the mouse barrel cortex. We find that both vertical and horizontal inputs show STDP, but that they display different time windows for induction of timing‐dependent long‐term depression (t‐LTD). Moreover, whereas t‐LTD at vertical inputs requires presynaptic NMDA receptors and is expressed presynaptically, using paired recordings we find that t‐LTD at horizontal inputs requires postsynaptic NMDA receptors and is expressed postsynaptically. These results demonstrate that similar forms of plasticity on the same postsynaptic neuron can be mediated by distinct mechanisms, and suggest that these forms of plasticity may enable these two types of cortical synapses to support different functions.
Timing‐dependent LTD (t‐LTD) at vertical inputs on layer 2/3 neurons (L4‐L2/3) requires presynaptic NMDA receptors and is expressed presynaptically, but little is known about these mechanisms at horizontal inputs (L2/3‐L2/3). Using paired recordings we demonstrate here that t‐LTD at L2/3‐L2/3 synapses also requires NMDA receptors but is induced and expressed postsynaptically. These results indicate that similar forms of plasticity on the same postsynaptic neuron may be mediated by distinct mechanisms and suggest that these forms of plasticity may support different developmental functions in the cortex.
PMCID: PMC4002250  PMID: 24760524
LTD; LTP; mouse; somatosensory cortex; STDP
8.  Distinct roles of GABAB1a- and GABAB1b-containing GABAB receptors in spontaneous and evoked termination of persistent cortical activity 
The Journal of Physiology  2012;591(Pt 4):835-843.
During slow-wave sleep, cortical neurons display synchronous fluctuations between periods of persistent activity (‘UP states’) and periods of relative quiescence (‘DOWN states’). Such UP and DOWN states are also seen in isolated cortical slices. Recently, we reported that both spontaneous and evoked termination of UP states in slices from the rat medial entorhinal cortex (mEC) involves GABAB receptors. Here, in order to dissociate the roles of GABAB1a- and GABAB1b-containing receptors in terminating UP states, we used mEC slices from mice in which either the GABAB1a or the GABAB1b subunit had been genetically ablated. Pharmacological blockade of GABAB receptors using the antagonist CGP55845 prolonged the UP state duration in both wild-type mice and those lacking the GABAB1b subunit, but not in those lacking the GABAB1a subunit. Conversely, electrical stimulation of layer 1 could terminate an ongoing UP state in both wild-type mice and those lacking the GABAB1a subunit, but not in those lacking the GABAB1b subunit. Together with previous reports, indicating a preferential presynaptic location of GABAB1a- and postsynaptic location of GABAB1b-containing receptors, these results suggest that presynaptic GABAB receptors contribute to spontaneous DOWN state transitions, whilst postsynaptic GABAB receptors are essential for the afferent termination of the UP state. Inputs to layer 1 from other brain regions could thus provide a powerful mechanism for synchronizing DOWN state transitions across cortical areas via activation of GABAergic interneurons targeting postsynaptic GABAB receptors.
PMCID: PMC3591701  PMID: 23266934
9.  Stem Cells Expanded from the Human Embryonic Hindbrain Stably Retain Regional Specification and High Neurogenic Potency 
The Journal of Neuroscience  2013;33(30):12407-12422.
Stem cell lines that faithfully maintain the regional identity and developmental potency of progenitors in the human brain would create new opportunities in developmental neurobiology and provide a resource for generating specialized human neurons. However, to date, neural progenitor cultures derived from the human brain have either been short-lived or exhibit restricted, predominantly glial, differentiation capacity. Pluripotent stem cells are an alternative source, but to ascertain definitively the identity and fidelity of cell types generated solely in vitro is problematic. Here, we show that hindbrain neuroepithelial stem (hbNES) cells can be derived and massively expanded from early human embryos (week 5–7, Carnegie stage 15–17). These cell lines are propagated in adherent culture in the presence of EGF and FGF2 and retain progenitor characteristics, including SOX1 expression, formation of rosette-like structures, and high neurogenic capacity. They generate GABAergic, glutamatergic and, at lower frequency, serotonergic neurons. Importantly, hbNES cells stably maintain hindbrain specification and generate upper rhombic lip derivatives on exposure to bone morphogenetic protein (BMP). When grafted into neonatal rat brain, they show potential for integration into cerebellar development and produce cerebellar granule-like cells, albeit at low frequency. hbNES cells offer a new system to study human cerebellar specification and development and to model diseases of the hindbrain. They also provide a benchmark for the production of similar long-term neuroepithelial-like stem cells (lt-NES) from pluripotent cell lines. To our knowledge, hbNES cells are the first demonstration of highly expandable neuroepithelial stem cells derived from the human embryo without genetic immortalization.
PMCID: PMC3721847  PMID: 23884946
10.  GluN2A and GluN2B subunit-containing NMDA receptors in hippocampal plasticity 
N-Methyl-d-aspartate receptor (NMDAR)-dependent synaptic plasticity is a strong candidate to mediate learning and memory processes that require the hippocampus. This plasticity is bidirectional, and how the same receptor can mediate opposite changes in synaptic weights remains a conundrum. It has been suggested that the NMDAR subunit composition could be involved. Specifically, one subunit composition of NMDARs would be responsible for the induction of long-term potentiation (LTP), whereas NMDARs with a different subunit composition would be engaged in the induction of long-term depression (LTD). Unfortunately, the results from studies that have investigated this hypothesis are contradictory, particularly in relation to LTD. Nevertheless, current evidence does suggest that the GluN2B subunit might be particularly important for plasticity and may make a synapse bidirectionally malleable. In particular, we conclude that the presence of GluN2B subunit-containing NMDARs at the postsynaptic density might be a necessary, though not a sufficient, condition for the strengthening of individual synapses. This is owing to the interaction of GluN2B with calcium/calmodulin-dependent protein kinase II (CaMKII) and is distinct from its contribution as an ion channel.
PMCID: PMC3843894  PMID: 24298164
NMDA receptor subunit; hippocampus; plasticity; learning
11.  Tau protein is required for amyloid β-induced impairment of hippocampal long-term potentiation 
Amyloid beta (Aβ) and tau protein are both implicated in memory impairment in mild cognitive impairment (MCI) and early Alzheimer’s disease (AD), but whether and how they interact is unknown. Consequently, here we asked if tau protein is required for the robust phenomenon of Aβ-induced impairment of hippocampal long-term potentiation (LTP), a widely accepted cellular model of memory. We used wild-type mice and mice with a genetic knockout of tau protein and recorded field potentials in an acute slice preparation. We demonstrate that the absence of tau protein prevents Aβ-induced impairment of LTP. Moreover, we show that Aβ increases tau phosphorylation and that a specific inhibitor of the tau kinase, glycogen synthase kinase 3 (GSK-3), blocks the increased tau phosphorylation induced by Aβ and prevents Aβ-induced impairment of LTP in wild-type mice. Together, these findings show that tau protein is required for Aβ to impair synaptic plasticity in the hippocampus and suggest that the Aβ-induced impairment of LTP is mediated by tau phosphorylation. We conclude that preventing the interaction between Aβ and tau could be a promising strategy for treating cognitive impairment in MCI and early AD.
PMCID: PMC3836238  PMID: 21289177
Alzheimer’s disease; beta amyloid; tau protein; LTP; hippocampus; mouse
12.  Priming of hippocampal population bursts by individual perisomatic-targeting interneurons 
Hippocampal population bursts (‘sharp wave-ripples’) occur during rest and slow-wave sleep and are thought to be important for memory consolidation. The cellular mechanisms involved are incompletely understood. Here we investigated the cellular mechanisms underlying the initiation of sharp waves using a hippocampal slice model. To this end, we used a combination of field recordings with planar multi-electrode arrays and whole-cell patch-clamp recordings of individual anatomically-identified pyramidal neurons and interneurons. We found that GABAA receptor-mediated inhibition is necessary for sharp wave generation. Moreover, the activity of individual perisomatic-targeting interneurons can both suppress, and subsequently enhance, the local generation of sharp waves. Finally, we show that this is achieved by the tight control of local excitation and inhibition by perisomatic-targeting interneurons. These results suggest that perisomatic-targeting interneurons assist in selecting the subset of pyramidal neurons that initiate each hippocampal sharp wave-ripple.
PMCID: PMC3763476  PMID: 20427657
sharp wave-ripples; population bursts; perisomatic-targeting interneurons; hippocampus; oscillations; Ca3
13.  Hemisphere-specific optogenetic stimulation reveals left-right asymmetry of hippocampal plasticity 
Nature neuroscience  2011;14(11):1413-1415.
Postsynaptic spines at CA3-CA1 synapses differ in glutamate receptor composition according to the hemispheric origin of CA3 afferents. To study the resulting functional consequences, we used optogenetic tools to selectively stimulate axons of CA3 pyramidal cells originating in either left or right mouse hippocampus. We found that left CA3 input produced more long-term potentiation at CA1 synapses than right CA3 input, due to differential expression of GluN2B subunit-containing NMDA receptors.
PMCID: PMC3754824  PMID: 21946328
STDP; LTP; Channelrhodopsin-2; hippocampus; mouse
14.  Presynaptic Self-Depression at Developing Neocortical Synapses 
Neuron  2013;77(1):35-42.
A central tenet of most theories of synaptic modification during cortical development is that correlated activity drives plasticity in synaptically connected neurons. Unexpectedly, however, using sensory-evoked activity patterns recorded from the developing mouse cortex in vivo, the synaptic learning rule that we uncover here relies solely on the presynaptic neuron. A burst of three presynaptic spikes followed, within a restricted time window, by a single presynaptic spike induces robust long-term depression (LTD) at developing layer 4 to layer 2/3 synapses. This presynaptic spike pattern-dependent LTD (p-LTD) can be induced by individual presynaptic layer 4 cells, requires presynaptic NMDA receptors and calcineurin, and is expressed presynaptically. However, in contrast to spike timing-dependent LTD, p-LTD is independent of postsynaptic and astroglial signaling. This spike pattern-dependent learning rule complements timing-based rules and is likely to play a role in the pruning of synaptic input during cortical development.
► Natural spike patterns in layer 4 neurons induce LTD at downstream synapses ► Spike pattern-dependent LTD can be induced in individual presynaptic neurons ► Spike pattern-dependent LTD requires presynaptic NMDA receptors and calcineurin ► Spike pattern-dependent LTD is independent of postsynaptic and astroglial signaling
Using natural spike patterns recorded from cortical layer 4 neurons in vivo, Rodríguez-Moreno et al. uncover a new spike pattern-dependent synaptic learning rule. They find that individual presynaptic neurons can drive NMDA receptor-dependent synaptic depression without a requirement for postsynaptic activity.
PMCID: PMC3542421  PMID: 23312514
15.  Frequency dependence of CA3 spike phase response arising from h-current properties 
The phase of firing of hippocampal neurons during theta oscillations encodes spatial information. Moreover, the spike phase response to synaptic inputs in individual cells depends on the expression of the hyperpolarization-activated mixed cation current (Ih), which differs between CA3 and CA1 pyramidal neurons. Here, we compared the phase response of these two cell types, as well as their intrinsic membrane properties. We found that both CA3 and CA1 pyramidal neurons show a voltage sag in response to negative current steps but that this voltage sag is significantly smaller in CA3 cells. Moreover, CA3 pyramidal neurons have less prominent resonance properties compared to CA1 pyramidal neurons. This is consistent with differential expression of Ih by the two cell types. Despite their distinct intrinsic membrane properties, both CA3 and CA1 pyramidal neurons displayed bidirectional spike phase control by excitatory conductance inputs during theta oscillations. In particular, excitatory inputs delivered at the descending phase of a dynamic clamp-induced membrane potential oscillation delayed the subsequent spike by nearly 50 mrad. The effect was shown to be mediated by Ih and was counteracted by increasing inhibitory conductance driving the membrane potential oscillation. Using our experimental data to feed a computational model, we showed that differences in Ih between CA3 and CA1 pyramidal neurons could predict frequency-dependent differences in phase response properties between these cell types. We confirmed experimentally such frequency-dependent spike phase control in CA3 neurons. Therefore, a decrease in theta frequency, which is observed in intact animals during novelty, might switch the CA3 spike phase response from unidirectional to bidirectional and thereby promote encoding of the new context.
PMCID: PMC3872302  PMID: 24399930
theta oscillation; phase response; Ih; resonance; hippocampus; CA3; CA1
16.  The Hodgkin-Huxley Heritage: From Channels to Circuits 
The Hodgkin-Huxley studies of the action potential, published 60 years ago, are a central pillar of modern neuroscience research, ranging from molecular investigations of the structural basis of ion channel function to the computational implications at circuit level. In this Symposium Review, we aim to demonstrate the ongoing impact of Hodgkin’s and Huxley’s ideas. The Hodgkin-Huxley model established a framework in which to describe the structural and functional properties of ion channels, including the mechanisms of ion permeation, selectivity, and gating. At a cellular level, the model is used to understand the conditions that control both the rate and timing of action potentials, essential for neural encoding of information. Finally, the Hodgkin-Huxley formalism is central to computational neuroscience to understand both neuronal integration and circuit level information processing, and how these mechanisms might have evolved to minimize energy cost.
PMCID: PMC3500626  PMID: 23055474
17.  Gating of NMDA receptor-mediated hippocampal spike timing-dependent potentiation by mGluR5 
Neuropharmacology  2012;63(4):701-709.
Hippocampal long-term potentiation (LTP) is believed to be important for learning and memory. Experimentally, the pairing of precisely timed pre- and postsynaptic spikes within a time window of ∼10 ms can induce timing-dependent LTP (tLTP), but the requirements for induction of tLTP change with development: in young rodents single postsynaptic spikes are sufficient to induce tLTP, whereas postsynaptic burst firing appears to be required in the adult. However, hippocampal neurons in vivo show theta-modulated single spike activities also in older hippocampus. Here we investigated the conditions for single spike pairing to induce tLTP at older CA3–CA1 synapses. We found that the pairing of single pre- and postsynaptic spikes could induce tLTP in older hippocampus when the postsynaptic neuronal membrane was depolarized and the pairing frequency exceeded ∼4 Hz. The spike frequency requirement is postsynaptic, as tLTP could still be induced with presynaptic stimulation at 1 Hz as long as the postsynaptic spike frequency exceeded ∼4 Hz, suggesting that postsynaptic theta-frequency activity is required for the successful induction of tLTP at older CA3–CA1 synapses. The induction of tLTP was blocked by an NMDA receptor antagonist and by the selective mGluR5 blockers, MPEP and MTEP, whereas activation of mGluR1 and mGluR5 by DHPG relieved the postsynaptic spike frequency requirement for tLTP induction. These results suggest that activation of mGluR5 during single-spike pairing at older CA3–CA1 synapses gates NMDA receptor-dependent tLTP.
► Single-spike pairing can induce tLTP at older hippocampal CA3–CA1 synapses. ► tLTP induction requires postsynaptic depolarization and postsynaptic spike rate >4 Hz. ► tLTP induction requires NMDA receptors and is gated by mGluR5.
PMCID: PMC3396853  PMID: 22652057
Hippocampus; mGluR5; Spike timing-dependent plasticity; CA1; Development; Rat
18.  Caged intracellular NMDA receptor blockers for the study of subcellular ion channel function 
We have previously synthesized a caged form of the use-dependent N-methyl-D-aspartate (NMDA) receptor ion channel blocker MK801 and used intracellular photolysis of this compound to demonstrate the subcellular location of NMDA receptor ion channels involved in synaptic plasticity. Here, we discuss considerations regarding the choice of caging molecule, synthesis and the potential uses for caged ion channel blockers in neurophysiology.
PMCID: PMC3419105  PMID: 22896783
NMDA; MK801; ion channel; cage; photolysis
19.  Transgenic Overexpression of the Type I Isoform of Neuregulin 1 Affects Working Memory and Hippocampal Oscillations but not Long-term Potentiation 
Cerebral Cortex (New York, NY)  2011;22(7):1520-1529.
Neuregulin 1 (NRG1) is a growth factor involved in neurodevelopment and plasticity. It is a schizophrenia candidate gene, and hippocampal expression of the NRG1 type I isoform is increased in the disorder. We have studied transgenic mice overexpressing NRG1 type I (NRG1tg-type I) and their wild-type littermates and measured hippocampal electrophysiological and behavioral phenotypes. Young NRG1tg-type I mice showed normal memory performance, but in older NRG1tg-type I mice, hippocampus-dependent spatial working memory was selectively impaired. Hippocampal slice preparations from NRG1tg-type I mice exhibited a reduced frequency of carbachol-induced gamma oscillations and an increased tendency to epileptiform activity. Long-term potentiation in NRG1tg-type I mice was normal. The results provide evidence that NRG1 type I impacts on hippocampal function and circuitry. The effects are likely mediated via inhibitory interneurons and may be relevant to the involvement of NRG1 in schizophrenia. However, the findings, in concert with those from other genetic and pharmacological manipulations of NRG1, emphasize the complex and pleiotropic nature of the gene, even with regard to a single isoform.
PMCID: PMC3377963  PMID: 21878485
gamma oscillation; hippocampus; neuregulin; schizophrenia; synaptic plasticity
20.  Differences in subthreshold resonance of hippocampal pyramidal cells and interneurons: the role of h-current and passive membrane characteristics 
The Journal of Physiology  2010;588(Pt 12):2109-2132.
The intrinsic properties of distinct types of neuron play important roles in cortical network dynamics. One crucial determinant of neuronal behaviour is the cell's response to rhythmic subthreshold input, characterised by the input impedance, which can be determined by measuring the amplitude and phase of the membrane potential response to sinusoidal currents as a function of input frequency. In this study, we determined the impedance profiles of anatomically identified neurons in the CA1 region of the rat hippocampus (pyramidal cells as well as interneurons located in the stratum oriens, including OLM cells, fast-spiking perisomatic region-targeting interneurons and cells with axonal arbour in strata oriens and radiatum). The basic features of the impedance profiles, as well as the passive membrane characteristics and the properties of the sag in the voltage response to negative current steps, were cell-type specific. With the exception of fast-spiking interneurons, all cell types showed subthreshold resonance, albeit with distinct features. The HCN channel blocker ZD7288 (10 μm) eliminated the resonance and changed the shape of the impedance curves, indicating the involvement of the hyperpolarisation-activated cation current Ih. Whole-cell voltage-clamp recordings uncovered differences in the voltage-dependent activation and kinetics of Ih between different cell types. Biophysical modelling demonstrated that the cell-type specificity of the impedance profiles can be largely explained by the properties of Ih in combination with the passive membrane characteristics. We conclude that differences in Ih and passive membrane properties result in a cell-type-specific response to inputs at given frequencies, and may explain, at least in part, the differential involvement of distinct types of neuron in various network oscillations.
PMCID: PMC2905616  PMID: 20421280
23.  From Invertebrate Olfaction to Human Cognition: Emerging Computational Functions of Synchronized Oscillatory Activity 
PMCID: PMC2911952  PMID: 16467511
cognition; memory; olfaction; network; oscillation; synchronization
24.  Natural patterns of activity and long-term synaptic plasticity 
Current opinion in neurobiology  2000;10(2):172-179.
Long-term potentiation (LTP) of synaptic transmission is traditionally elicited by massively synchronous, high-frequency inputs, which rarely occur naturally. Recent in vitro experiments have revealed that both LTP and long-term depression (LTD) can arise by appropriately pairing weak synaptic inputs with action potentials in the postsynaptic cell. This discovery has generated new insights into the conditions under which synaptic modification may occur in pyramidal neurons in vivo. First, it has been shown that the temporal order of the synaptic input and the postsynaptic spike within a narrow temporal window determines whether LTP or LTD is elicited, according to a temporally asymmetric Hebbian learning rule. Second, backpropagating action potentials are able to serve as a global signal for synaptic plasticity in a neuron compared with local associative interactions between synaptic inputs on dendrites. Third, a specific temporal pattern of activity — postsynaptic bursting — accompanies synaptic potentiation in adults.
PMCID: PMC2900254  PMID: 10753798
25.  α5 Subunit-containing GABAA receptors mediate a slowly decaying inhibitory synaptic current in CA1 pyramidal neurons following Schaffer collateral activation 
Neuropharmacology  2010;58(3):668-675.
GABAA receptors that contain the α5 subunit (α5GABAARs) are highly expressed in the hippocampus, and have been implicated in learning and memory processes. They generate a tonic form of inhibition that regulates neuronal excitability. Recently it was shown that α5GABAARs also contribute to slow phasic inhibition of CA1 pyramidal neurons following local stimulation in the stratum lacunosum moleculare. However, it is unknown whether α5GABAARs can also be recruited indirectly by stimulation of Schaffer collaterals. Here, we studied GABAergic currents evoked by stimulation in the stratum radiatum of CA1 in the presence and absence of CNQX to block AMPA receptor-mediated excitation. We tested their sensitivity to gabazine and two drugs acting at the benzodiazepine site of α1/α2/α3 or α5GABAARs (400 nM zolpidem and 20 nM L-655,708, respectively). IPSCs evoked by stimulation in the stratum radiatum in the presence of CNQX were potentiated by zolpidem, blocked by 1 μM gabazine and were relatively insensitive to L-655,708 consistent with the lack of α5GABAARs. In contrast, IPSCs evoked by stimulation of Schaffer collaterals had a significant gabazine-insensitive component. This component was attenuated by L-655,708 and enhanced by burst stimulation. Furthermore, the L-655,708-sensitive current was absent in recordings from mice lacking α5GABAARs (gabra5−/− mice). These results show that α5GABAAR-mediated phasic inhibition is activated by the Schaffer collateral pathway and provide evidence for activity pattern-dependent participation of α5GABAARs in inhibition.
PMCID: PMC2814005  PMID: 19941877
α5; GABAA receptor; Hippocampus; Inhibition; Mouse; Rat; Schaffer collateral

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