Biology subjects

Madison, D. V.

Publications and source records attributed to Madison, D. V..

7 recordsLinked to original sources

bioRxiv2021

Extensive structural remodeling of the axonal arbors of parvalbumin basket cells during development

Parvalbumin-containing (PV+) basket cells are specialized cortical interneurons that regulate the activity of local neuronal circuits with high temporal precision and reliability. PV+ interneuron disfunction is associated with numerous psychiatric disorders, including schizophrenia and autism spectrum disorders. To understand how the PV+ interneuron connectivity underlying their functional properties is established during development, we used array tomography to map pairs of synaptically connected PV+ interneurons and postsynaptic neurons from the neocortex of mice of both sexes. We focused on the axon-myelin unit of the PV+ interneuron and quantified the number of synapses onto the postsynaptic neuron, length of connecting axonal paths, and their myelination at different time points between 2 weeks and 7 months of age. We find that myelination of the proximal axon occurs very rapidly during the third postnatal week and precedes a massive synapse pruning which takes place in the 4th postnatal week leading to about three-fold reduction of synaptic contacts made by the PV+ interneuron on its postsynaptic partner. Autapses, the synapses that PV+ interneurons form on themselves, however, are not subjected to pruning. Axon reorganizations continue beyond postnatal month 2, with the postsynaptic targets of PV+ interneurons gradually shifting to more proximal locations, and the length of axonal paths and their myelin becoming conspicuously uniform per connection. These continued microcircuit refinements likely provide the structural substrate for the robust inhibitory effects and fine temporal precision of PV+ basket cells. Significance statementThe axon of adult parvalbumin-containing (PV+) interneurons is highly specialized for fast and reliable neurotransmission. It is myelinated and forms synapses mostly onto the cell bodies and proximal dendrites of postsynaptic neurons for maximal impact. In this study we follow the development of the PV+ interneuron axon, its myelination and synapse formation, revealing a rapid sequence of axonal reorganization, myelination of the PV+ interneuron proximal axon, and subsequent pruning of almost two-thirds of the synapses in an individual connection. This is followed by a prolonged period of axon refinement and additional myelination leading to a remarkable precision of connections in the adult mouse cortex, consistent with the temporal precision and fidelity of PV+ interneuron action.

neuroscience↗

bioRxiv2020

Conduction velocity along the local axons of parvalbumin interneurons correlates with the degree of axonal myelination

Parvalbumin-containing (PV+) basket cells in mammalian neocortex are fast-spiking interneurons that regulate the activity of local neuronal circuits in multiple ways. Even though PV+ basket cells are locally projecting interneurons, their axons are myelinated. Can this myelination contribute in any significant way to the speed of action potential propagation along such short axons? We used dual whole cell recordings of synaptically connected PV+ interneurons and their postsynaptic target in acutely-prepared neocortical slices from adult mice to measure the amplitude and latency of single presynaptic action potential-evoked inhibitory postsynaptic currents (IPSCs). These same neurons were then imaged with immunofluorescent array tomography, the synaptic contacts between them identified and a precise map of the connections was generated, with the exact axonal length and extent of myelin coverage. Our results support that myelination of PV+ basket cells significantly increases conduction velocity, and does so to a degree that can be physiologically relevant.

neuroscience↗

bioRxiv2020

Spike-frequency dependent inhibition and potentiation of neural activity by ultrasound

Ultrasound can modulate action-potential firing in vivo and in vitro, but the mechanistic basis of this phenomenon is not well understood. To address this problem, we used patch-clamp recording to quantify the effects of focused, high-frequency (43 MHz) ultrasound on evoked action potential firing in CA1 pyramidal neurons in acute rodent hippocampal brain slices. We find that ultrasound can either inhibit or potentiate firing in a spike-frequency-dependent manner: at low (near-threshold) input currents and low firing frequencies, ultrasound inhibits firing, while at higher input currents and higher firing frequencies, ultrasound potentiates firing. The net result of these two competing effects is that ultrasound increases the threshold current for action potential firing, the slope of frequency-input curves, and the maximum firing frequency. In addition, ultrasound slightly hyperpolarizes the resting membrane potential, decreases action potential width, and increases the depth of the afterhyperpolarization. All of these results can be explained by the hypothesis that ultrasound activates a sustained potassium conductance. According to this hypothesis, increased outward potassium currents hyperpolarize the resting membrane potential and inhibit firing at near-threshold input currents, but potentiate firing in response to higher input currents by limiting inactivation of voltage-dependent sodium channels during the action potential. This latter effect is a consequence of faster action-potential repolarization, which limits inactivation of voltage-dependent sodium channels, and deeper (more negative) afterhyperpolarization, which increases the rate of recovery from inactivation. Based on these results we propose that ultrasound activates thermosensitive and mechanosensitive two-pore-domain potassium (K2P) channels, through heating or mechanical effects of acoustic radiation force. Finite-element modelling of the effects of ultrasound on brain tissue suggests that the effects of ultrasound on firing frequency are caused by a small (less than 2{degrees}C) increase in temperature, with possible additional contributions from mechanical effects SUMMARYPrieto et al. describe how ultrasound can either inhibit or potentiate action potential firing in hippocampal pyramidal neurons and demonstrate that these effects can be explained by increased potassium conductance.

neuroscience↗

bioRxiv2020

Control of E-S Potentiation at two different sites in the dendro-somatic axis

EPSP-Spike (E-S) Potentiation occurs alongside synaptic Long-Term Potentiation (LTP), both triggered by high-frequency synaptic stimulation (HFS). In this study, we confirm the earlier findings that E-S potentiation appears to be prevented by prior reduction of GABAA receptor-mediated inhibitory synaptic transmission. However, we demonstrate that this is a result of an occlusion of E-S potentiation, not a block. E-S potentiation and GABAA antagonism each saturate postsynaptic action potential discharge, but E-S potentiation can still be induced by high frequency activation of synapses, even in the presence of pharmacological GABAA blockade. These results suggest that GABAA blockers/antagonists and E-S potentiation share an expression mechanism, namely the reduction of GABAA-mediated synaptic inhibition. We also assayed changes in the electrical coupling between dendrite and soma, and were surprised to find that this coupling is decreased following HFS, a change that would oppose E-S potentiation. This decrease in dendritic-soma electrical coupling (D-S coupling) was induced through the action of GABAB receptors, but not maintained or expressed via the activity of these receptors. These data all together suggest that there are two distinct and opposing changes that occur as a result of HFS: 1) A decrease in passive dendro-somatic electrical coupling, and 2), an increase in coupling between the somatic EPSP and action potential generation. These two opposing influences may function as a homeostatic mechanism to balance the excitatory/inhibitory relationship between primary neurons and interneurons, and may represent a separate mechanism by which feedback and feed-forward synaptic inhibition can influence E-S coupling in opposite directions. Significance statementE-S Potentiation is an activity-dependent form of plasticity that boosts the efficiency of the coupling between synaptic input and action potential output in a neuron. Because it is induced by synaptic activity in series with the more familiar long-term potentiation (LTP), and is similarly persistent, it represents an additional mechanism by which memory traces may be stored within neural circuits. The significance of this paper is that it shows that there are at least two points of control for E-S potentiation which influence it in opposite directions, thereby providing additional basic mechanisms by which memory traces may be modulated.

neuroscience↗

bioRxiv2019

Multifaceted Changes in Synaptic Composition and Astrocytic Involvement in a Mouse Model of Fragile X Syndrome

Fragile X Syndrome (FXS), a common inheritable form of intellectual disability, is known to alter neocortical circuits. However, its impact on the diverse synapse types comprising these circuits, or on the involvement of astrocytes, is not well known. We used immunofluorescent array tomography to quantify different synaptic populations and their association with astrocytes in layers 1 through 4 of the adult somatosensory cortex of a FXS mouse model, the FMR1 knockout mouse. The collected multi-channel data contained approximately 1.6 million synapses which were analyzed using a probabilistic synapse detector. Our study reveals complex, synapse-type and layer specific changes in the neocortical circuitry of FMR1 knockout mice. In layers 1 and 2/3, there is a significant decrease in the density of excitatory glutamatergic synapses, both VGluT1 and VGluT2 type, and their association with astrocytes, while the changes in inhibitory GABAergic synapses are less pronounced. Meanwhile in layer 4, there is a significant increase in the density of small VGluT1 synapses, with no changes in the astrocytic association of synapses. The ability to dissect the circuit deficits by synapse type and astrocytic involvement, will be crucial for understanding how these changes affect circuit function, and ultimately define targets for therapeutic intervention.

neuroscience↗

bioRxiv2019

Differential Inhibition of E-S Potentiation and Long-term Potentiation by Cell-derived and Arctic Amyloid Beta

Soluble oligomers of amyloid-beta peptide (Abeta) have been implicated in the onset of memory deficits in Alzheimers disease, perhaps due to their reported ability to impair long-term potentiation (LTP) of synaptic strength. We previously showed the effect of Abeta on LTP depends on the strength of LTP induction. Furthermore, Abeta affects EPSP-Spike (E-S) potentiation more robustly than LTP, suggesting that E-S potentiation may be equally important to learning and memory in the context of Alzheimers disease. Here we extend our findings to two additional forms of Abeta that form higher concentrations of soluble Abeta oligomers and show that they also affect E-S potentiation at induction strengths where there is no effect on LTP in hippocampal slices.

neuroscience↗

bioRxiv2018

Myelinated inhibitory axons in human neocortex

Numerous myelinated axons traverse the human neocortex. In a previous paper (Micheva et al., 2016) we showed that in mouse many of these axons belong to local inhibitory neurons, the parvalbumin-positive basket cells. Here, using samples of neurosurgically-excised cortex, we confirm the presence of myelinated inhibitory axons in all layers of human neocortex. As in mouse, these axons have distinctive features, including high neurofilament content, short nodes of Ranvier, and high content of myelin basic protein in their myelin sheath. We further show that, consistent with the known high-energy demands of parvalbumin interneurons, the inhibitory myelinated axons have more mitochondria, as well more 2,3-cyclic nucleotide 3-phosphodiesterase (a protein enriched in the myelin cytoplasmic channels thought to provide access for trophic support from oligodendrocytes). The distinctive features of myelinated inhibitory axons in human cortical grey matter may have important implications for neurological disorders that involve pathologies of myelinated axons.

neuroscience↗