ORCID Profile
0000-0002-0986-6260
Current Organisations
University of Tasmania
,
Australian National University
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Publisher: Society for Neuroscience
Date: 16-08-2006
DOI: 10.1523/JNEUROSCI.1088-06.2006
Abstract: Stargazer ( stg ) mutant mice fail to express stargazin [transmembrane AMPA receptor regulatory protein γ2 (TARPγ2)] and consequently experience absence seizure-like thalamocortical spike-wave discharges that pervade the hippoc al formation via the dentate gyrus (DG). As in other seizure models, the dentate granule cells of stg develop elaborate reentrant axon collaterals and transiently overexpress brain-derived neurotrophic factor. We investigated whether GABAergic parameters were affected by the stg mutation in this brain region. GABA A receptor (GABAR) α4 and β3 subunits were consistently upregulated, GABAR δ expression appeared to be variably reduced, whereas GABAR α1, β2, and γ2 subunits and the GABAR synaptic anchoring protein gephyrin were essentially unaffected. We established that the α4βγ2 subunit-containing, flunitrazepam-insensitive subtype of GABARs, not normally a significant GABAR in DG neurons, was strongly upregulated in stg DG, apparently arising at the expense of extrasynaptic α4βδ-containing receptors. This change was associated with a reduction in neurosteroid-sensitive GABAR-mediated tonic current. This switch in GABAR subtypes was not reciprocated in the tottering mouse model of absence epilepsy implicating a unique, intrinsic adaptation of GABAergic networks in stg . Contrary to previous reports that suggested that TARPγ2 is expressed in the dentate, we find that TARPγ2 was neither detected in stg nor control DG. We report that TARPγ8 is the principal TARP isoform found in the DG and that its expression is compromised by the stargazer mutation. These effects on GABAergic parameters and TARPγ8 expression are likely to arise as a consequence of failed expression of TARPγ2 elsewhere in the brain, resulting in hyperexcitable inputs to the dentate.
Publisher: Springer New York
Date: 2014
Publisher: Frontiers Media SA
Date: 2016
Publisher: Cold Spring Harbor Laboratory
Date: 16-10-2021
DOI: 10.1101/2021.10.15.464378
Abstract: A long-range circuit linking anterior cingulate cortex (ACC) to primary visual cortex (V1) has been previously proposed to mediate visual selective attention in mice during visually guided behaviour. Here we used in vivo two-photon functional imaging to measure endogenous activity of ACC neurons projecting to layer 1 of V1 (ACC-V1 axons ) in mice either passively viewing stimuli or performing a go/no-go visually guided task. We observed that while ACC-V1 axons were recruited under these conditions, this was not linked to enhancement of neural or behavioural measures of sensory coding. Instead, ACC-V1 axon activity was observed to be associated with licking behaviour, modulated by reward, and biased towards task relevant sensory cortex.
Publisher: Elsevier BV
Date: 06-2022
Publisher: Wiley
Date: 08-04-2009
Publisher: Society for Neuroscience
Date: 30-03-2016
DOI: 10.1523/JNEUROSCI.3836-15.2016
Abstract: Thalamocortical neurons have thousands of synaptic connections from layer VI corticothalamic neurons distributed across their dendritic trees. Although corticothalamic synapses provide significant excitatory input, it remains unknown how different spatial and temporal input patterns are integrated by thalamocortical neurons. Using dendritic recording, 2-photon glutamate uncaging, and computational modeling, we investigated how rat dorsal lateral geniculate nucleus thalamocortical neurons integrate excitatory corticothalamic feedback. We find that unitary corticothalamic inputs produce small somatic EPSPs whose litudes are passively normalized and virtually independent of the site of origin within the dendritic tree. Furthermore, uncaging of MNI glutamate reveals that thalamocortical neurons have postsynaptic voltage-dependent mechanisms that can lify integrated corticothalamic input. These mechanisms, involving NMDA receptors and T-type Ca 2+ channels, require temporally synchronous synaptic activation but not spatially coincident input patterns. In hyperpolarized thalamocortical neurons, T-type Ca 2+ channels produce nonlinear lification of temporally synchronous inputs, whereas asynchronous inputs are not lified. At depolarized potentials, the input–output function for synchronous synaptic input is linear but shows enhanced gain due to activity-dependent recruitment of NMDA receptors. Computer simulations reveal that EPSP lification by T-type Ca 2+ channels and NMDA receptors occurs when synaptic inputs are either clustered onto in idual dendrites or when they are distributed throughout the dendritic tree. Consequently, postsynaptic EPSP lification mechanisms limit the “modulatory” effects of corticothalamic synaptic inputs on thalamocortical neuron membrane potential and allow these synapses to act as synchrony-dependent “drivers” of thalamocortical neuron firing. These complex thalamocortical input–output transformations significantly increase the influence of corticothalamic feedback on sensory information transfer. SIGNIFICANCE STATEMENT Neurons in first-order thalamic nuclei transmit sensory information from the periphery to the cortex. However, the numerically dominant synaptic input to thalamocortical neurons comes from the cortex, which provides a strong, activity-dependent modulatory feedback influence on information flow through the thalamus. Here, we reveal how in idual quantal-sized corticothalamic EPSPs propagate within thalamocortical neuron dendrites and how different spatial and temporal input patterns are integrated by these cells. We find that thalamocortical neurons have voltage- and synchrony-dependent postsynaptic mechanisms, involving NMDA receptors and T-type Ca 2+ channels that allow nonlinear lification of integrated corticothalamic EPSPs. These mechanisms significantly increase the responsiveness of thalamocortical neurons to cortical excitatory input and broaden the “modulatory” influence exerted by corticothalamic synapses.
Publisher: Elsevier BV
Date: 07-2019
DOI: 10.1016/J.NEURON.2019.06.019
Abstract: While many studies indicate that dendrites can perform a range of local computations on their inputs, work from the Harnett lab in this issue of Neuron suggests that the vast majority of active dendritic events are synchronized across the somato-dendritic axis of cortical pyramidal neurons.
Publisher: Society for Neuroscience
Date: 03-11-2010
DOI: 10.1523/JNEUROSCI.3895-10.2010
Abstract: Inhibitory projections from the striatum and globus pallidus converge onto GABAergic projection neurons of the substantia nigra pars reticulata (SNr). Based on existing structural and functional evidence, these pathways are likely to differentially regulate the firing of SNr neurons. We sought to investigate the functional differences in inhibitory striatonigral and pallidonigral traffic using whole-cell voltage cl in brain slices with these pathways preserved. We found that striatonigral IPSCs exhibited a high degree of paired-pulse facilitation. We tracked this facilitation over development and found the facilitation as the animal aged, but stabilized by postnatal day 17 (P17), with a paired pulse ratio of 2. We also found that the recovery from facilitation accelerated over development, again, reaching a stable phenotype by P17. In contrast, pallidonigral synapses show paired-pulse depression, and this depression could be solely explained by presynaptic changes. The mean paired-pulse ratio of 0.67 did not change over development, but the recovery from depression slowed over development. Pallidonigral IPSCs were significantly faster than striatonigral IPSCs when measured at the soma. Finally, under current cl , prolonged bursts of striatal IPSPs were able to consistently silence the pacemaker activity of nigral neurons, whereas pallidal inputs depressed, allowing nigral neurons to reinstate firing. These findings highlight the importance of differential dynamics of neurotransmitter release in regulating the circuit behavior of the basal ganglia.
Publisher: Wiley
Date: 23-04-2018
DOI: 10.1111/CNS.12858
Publisher: Cold Spring Harbor Laboratory
Date: 06-03-2020
DOI: 10.1101/2020.03.05.979724
Abstract: The development of new high throughput approaches for neuroscience such as high-density silicon probes and 2-photon imaging have led to a renaissance in visual neuroscience. However, generating the stimuli needed to evoke activity in the visual system still represents a non-negligible difficulty for experimentalists. While several widely used software toolkits exist to deliver such stimuli, they all suffer from some shortcomings. Primarily, the hardware needed to effectively display such stimuli comes at a significant financial cost, and secondly, triggering and/or timing the stimuli such that it can be accurately synchronized with other devices requires the use of legacy hardware, further hardware, or bespoke solutions. Here we present RPG, a Python package written for the Raspberry Pi, which overcomes these issues. Specifically, the Raspberry Pi is a low-cost, credit card sized computer with general purpose input/output pins, allowing RPG to be triggered to deliver stimuli and to provide real-time feedback on stimulus timing. RPG delivers stimuli at frames per second and the feedback of frame timings is accurate to 10s of microseconds. We provide a simple to use Python interface that is capable of generating drifting sine wave gratings, Gabor patches and displaying raw images/video.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 03-2017
DOI: 10.1097/AJP.0000000000000390
Abstract: Previous studies have demonstrated the presence of active trigger points (TrPs) in women with migraine reproducing their headache attacks. No study has investigated whether these TrPs can alter cervical muscle function in migraine. Our objective was to analyze differences in the activation of superficial neck flexor and extensor muscles in women with migraine considering the presence of active TrPs in the splenius capitis (SC), the upper trapezius (UT), and the sternocleidomastoid (SCM) muscles. Surface electromyography (EMG) was recorded from the superficial flexors (SCM and anterior scalene) and the extensor (SC, UT) muscles bilaterally as participants performed a staged task of cranio-cervical flexion (CCF 5 contractions representing a progressive increase in CCF range of motion) in 70 women with migraine. They were stratified according to the presence or the absence of active TrPs in the SCM, the SC, or the UT musculature. A comparison of EMG normalized root mean square (RMS) values was conducted with a 2×5 analysis of covariance with the task level as the within-subject variable, group stratified by active TrPs as the between-subjects variable and the presence of neck pain as a covariable. All patients exhibited active TrPs in their cervical muscles, which reproduced their migraine. Women with migraine exhibiting active TrPs in the SCM ( P .01), the UT ( P .05), or the SC ( P .05) muscles had lower normalized RMS values of their superficial neck flexors than those without active TrPs in the same muscles. In addition, in iduals exhibiting active TrPs in the SC and the UT (both, P .05) muscles had higher normalized RMS values in the SC muscle than those without active TrPs in the same muscles. The presence of active TrPs in the cervical musculature determines an altered activation of superficial neck and extensor muscles during low-load, isometric CCF contractions in women with migraine.
Publisher: Wiley
Date: 14-06-2010
Publisher: Elsevier BV
Date: 10-2007
Publisher: Society for Neuroscience
Date: 25-11-2015
DOI: 10.1523/JNEUROSCI.2740-15.2015
Abstract: Low-threshold Ca 2+ spikes (LTS) are an indispensible signaling mechanism for neurons in areas including the cortex, cerebellum, basal ganglia, and thalamus. They have critical physiological roles and have been strongly associated with disorders including epilepsy, Parkinson's disease, and schizophrenia. However, although dendritic T-type Ca 2+ channels have been implicated in LTS generation, because the properties of low-threshold spiking neuron dendrites are unknown, the precise mechanism has remained elusive. Here, combining data from fluorescence-targeted dendritic recordings and Ca 2+ imaging from low-threshold spiking cells in rat brain slices with computational modeling, the cellular mechanism responsible for LTS generation is established. Our data demonstrate that key somatodendritic electrical conduction properties are highly conserved between glutamatergic thalamocortical neurons and GABAergic thalamic reticular nucleus neurons and that these properties are critical for LTS generation. In particular, the efficiency of soma to dendrite voltage transfer is highly asymmetric in low-threshold spiking cells, and in the somatofugal direction, these neurons are particularly electrotonically compact. Our data demonstrate that LTS have remarkably similar litudes and occur synchronously throughout the dendritic tree. In fact, these Ca 2+ spikes cannot occur locally in any part of the cell, and hence we reveal that LTS are generated by a unique whole-cell mechanism that means they always occur as spatially global spikes. This all-or-none, global electrical and biochemical signaling mechanism clearly distinguishes LTS from other signals, including backpropagating action potentials and dendritic Ca 2+ /NMDA spikes, and has important consequences for dendritic function in low-threshold spiking neurons. SIGNIFICANCE STATEMENT Low-threshold Ca 2+ spikes (LTS) are critical for important physiological processes, including generation of sleep-related oscillations, and are implicated in disorders including epilepsy, Parkinson's disease, and schizophrenia. However, the mechanism underlying LTS generation in neurons, which is thought to involve dendritic T-type Ca 2+ channels, has remained elusive due to a lack of knowledge of the dendritic properties of low-threshold spiking cells. Combining dendritic recordings, two-photon Ca 2+ imaging, and computational modeling, this study reveals that dendritic properties are highly conserved between two prominent low-threshold spiking neurons and that these properties underpin a whole-cell somatodendritic spike generation mechanism that makes the LTS a unique global electrical and biochemical signal in neurons.
Publisher: Springer New York
Date: 2014
Publisher: Frontiers Media SA
Date: 2013
Publisher: American Physiological Society
Date: 11-2014
Abstract: Thalamocortical neurons integrate sensory and cortical activity and are regulated by input from inhibitory neurons in the thalamic reticular nucleus. Evidence suggests that during bursts of action potentials, dendritic calcium transients are seen throughout the dendritic tree of thalamocortical cells. Here, we review a recent study that suggests these calcium transients regulate inhibitory input, and we attempt to reconcile studies that differ on which ion channels are the source of the calcium.
Publisher: Society for Neuroscience
Date: 27-04-2017
DOI: 10.1523/JNEUROSCI.0015-17.2017
Abstract: Backpropagating action potentials (bAPs) are indispensable in dendritic signaling. Conflicting Ca 2+ -imaging data and an absence of dendritic recording data means that the extent of backpropagation in thalamocortical (TC) and thalamic reticular nucleus (TRN) neurons remains unknown. Because TRN neurons signal electrically through dendrodendritic gap junctions and possibly via chemical dendritic GABAergic synapses, as well as classical axonal GABA release, this lack of knowledge is problematic. To address this issue, we made two-photon targeted patch-cl recordings from rat TC and TRN neuron dendrites to measure bAPs directly. These recordings reveal that “tonic”' and low-threshold-spike (LTS) “burst” APs in both cell types are always recorded first at the soma before backpropagating into the dendrites while undergoing substantial distance-dependent dendritic litude attenuation. In TC neurons, bAP attenuation strength varies according to firing mode. During LTS bursts, somatic AP half-width increases progressively with increasing spike number, allowing late-burst spikes to propagate more efficiently into the dendritic tree compared with spikes occurring at burst onset. Tonic spikes have similar somatic half-widths to late burst spikes and undergo similar dendritic attenuation. In contrast, in TRN neurons, AP properties are unchanged between LTS bursts and tonic firing and, as a result, distance-dependent dendritic attenuation remains consistent across different firing modes. Therefore, unlike LTS-associated global electrical and calcium signals, the spatial influence of bAP signaling in TC and TRN neurons is more restricted, with potentially important behavioral-state-dependent consequences for synaptic integration and plasticity in thalamic neurons. SIGNIFICANCE STATEMENT In most neurons, action potentials (APs) initiate in the axosomatic region and propagate into the dendritic tree to provide a retrograde signal that conveys information about the level of cellular output to the locations that receive most input: the dendrites. In thalamocortical and thalamic reticular nucleus neurons, the site of AP generation and the true extent of backpropagation remain unknown. Using patch-cl recordings, this study measures dendritic propagation of APs directly in these neurons. In either cell type, high-frequency low-threshold spike burst or lower-frequency tonic APs undergo substantial voltage attenuation as they spread into the dendritic tree. Therefore, backpropagating spikes in these cells can only influence signaling in the proximal part of the dendritic tree.
Publisher: Society for Neuroscience
Date: 05-2019
DOI: 10.1523/ENEURO.0364-18.2019
Abstract: Copy number variation (CNV) at chromosomal region 15q11.2 is linked to increased risk of neurodevelopmental disorders including autism and schizophrenia. A significant gene at this locus is cytoplasmic fragile X mental retardation protein (FMRP) interacting protein 1 ( CYFIP1 ). CYFIP1 protein interacts with FMRP, whose monogenic absence causes fragile X syndrome (FXS). Fmrp knock-out has been shown to reduce tonic GABAergic inhibition by interacting with the δ-subunit of the GABA A receptor (GABA A R). Using in situ hybridization (ISH), qPCR, Western blotting techniques, and patch cl electrophysiology in brain slices from a Cyfip1 haploinsufficient mouse, we examined δ-subunit mediated tonic inhibition in the dentate gyrus (DG). In wild-type (WT) mice, DG granule cells (DGGCs) responded to the δ-subunit-selective agonist THIP with significantly increased tonic currents. In heterozygous mice, no significant difference was observed in THIP-evoked currents in DGGCs. Phasic GABAergic inhibition in DGGC was also unaltered with no difference in properties of spontaneous IPSCs (sIPSCs). Additionally, we demonstrate that DG granule cell layer (GCL) parvalbumin-positive interneurons (PV + -INs) have functional δ-subunit-mediated tonic GABAergic currents which, unlike DGGC, are also modulated by the α 1 -selective drug zolpidem. Similar to DGGC, both IPSCs and THIP-evoked currents in PV + -INs were not different between Cyfip1 heterozygous and WT mice. Supporting our electrophysiological data, we found no significant change in hippoc al δ-subunit mRNA expression or protein level and no change in α 1 /α 4 -subunit mRNA expression. Thus, Cyfip1 haploinsufficiency, mimicking human 15q11.2 microdeletion syndrome, does not alter hippoc al phasic or tonic GABAergic inhibition, substantially differing from the Fmrp knock-out mouse model.
Publisher: Elsevier BV
Date: 03-2009
DOI: 10.1016/J.BRAINRESBULL.2008.12.005
Abstract: Preparations of Ficus platyphylla have been used in Nigerian traditional medicine for the management of epilepsy for many years and their efficacy is widely acclaimed among the Hausa communities of northern Nigeria. The anticonvulsant properties of the saponin rich fraction (SFG) obtained from the methanol extract of F. platyphylla stem bark were studied on pentylenetetrazole-, strychnine- and maximal electroshock seizures in mice. Effects of SFG were also examined in murine models for neurological disease and on relevant in vitro targets for anticonvulsant drugs. SFG protected mice against pentylenetetrazole- and strychnine-induced seizures and significantly delayed the onset of myoclonic jerks and tonic seizures. SFG failed to protect mice against maximal electroshock seizures at doses tested. SFG neither abolished the spontaneous discharges induced by 4-aminopyridine in a neonatal rat brain slice model of tonic-clonic epilepsy nor could it modulate chloride currents through GABA(A) receptor channel complex in cultured cortical cells. However, it was able to non-selectively suppress excitatory and inhibitory synaptic traffic, blocked sustained repetitive firing (SRF) and spontaneous action potential firing in these cultured cells. Our results provide scientific evidence that F. platyphylla stem bark may contain psychoactive principles with potential anticonvulsant properties. SFG impaired membrane excitability a property shared by most anticonvulsants particularly the voltage-gated sodium channel (VGSC) blocking drugs, thus supporting the isolation and development of the saponin components of this plant as anticonvulsant agents.
Publisher: Public Library of Science (PLoS)
Date: 28-02-2014
Publisher: Society for Neuroscience
Date: 08-04-2015
DOI: 10.1523/JNEUROSCI.3603-14.2015
Abstract: During sleep and anesthesia, neocortical neurons exhibit rhythmic UP/DOWN membrane potential states. Although UP states are maintained by synaptic activity, the mechanisms that underlie the initiation and robust rhythmicity of UP states are unknown. Using a physiologically validated model of UP/DOWN state generation in mouse neocortical slices whereby the cholinergic tone present in vivo is reinstated, we show that the regular initiation of UP states is driven by an electrophysiologically distinct subset of morphologically identified layer 5 neurons, which exhibit intrinsic rhythmic low-frequency burst firing at ∼0.2–2 Hz. This low-frequency bursting is resistant to block of glutamatergic and GABAergic transmission but is absent when slices are maintained in a low Ca 2+ medium (an alternative, widely used model of cortical UP/DOWN states), thus explaining the lack of rhythmic UP states and abnormally prolonged DOWN states in this condition. We also characterized the activity of various other pyramidal and nonpyramidal neurons during UP/DOWN states and found that an electrophysiologically distinct subset of layer 5 regular spiking pyramidal neurons fires earlier during the onset of network oscillations compared with all other types of neurons recorded. This study, therefore, identifies an important role for cell-type-specific neuronal activity in driving neocortical UP states.
No related grants have been discovered for William Connelly.