Biology subjects

Mitchell, D. E.

Publications and source records attributed to Mitchell, D. E..

4 recordsLinked to original sources

bioRxiv2022

Altered integration of excitatory inputs onto the basal dendrites of layer 5 pyramidal neurons in a mouse model of Fragile X Syndrome

To uncover how synaptic integration of feedforward sensory inputs is affected in autism spectrum disorders (ASD), we used two-photon uncaging of caged glutamate to activate two clustered spines in the basal dendrites of layer 5 (L5) pyramidal neurons from a mouse model of Fragile X syndrome (FXS), the most common genetic cause of ASD. While subthreshold excitatory inputs integrate linearly in wild-type animals, surprisingly those with FXS summate sublinearly, contradicting what would be expected of a hyperexcitable cortex typically associated with ASD. Knockdown of the regulatory {beta}4 subunit of BK channels, rescues the synaptic integration, a result that was corroborated with numerical simulations. Taken together, these findings suggest that there is a differential impairment in the integration of feedforward sensory and feedback predictive inputs in L5 pyramidal neurons in FXS and potentially other forms of ASD. These results challenge the traditional view that FXS and other ASD are characterized by sensory hypersensitivity, but instead by hyposensitivity of sensory inputs and hypersensitivity of predictive inputs onto cortical neurons.

neuroscience↗

bioRxiv2021

Selective activation of BK channels in small-headed dendritic spines suppresses excitatory postsynaptic potentials

Dendritic spines are the main receptacles of excitatory information in the brain. Their particular morphology, with a small head connected to the dendrite by a slender neck, has inspired theoretical and experimental work to understand how these structural features affect the processing, storage and integration of synaptic inputs in pyramidal neurons (PNs). The activation of glutamate receptors in spines triggers a large voltage change as well as calcium signals at the spine head. Thus, voltage-gated and calcium-activated potassium channels located in the spine head likely play a key role in synaptic transmission. Here we study the presence and function of large conductance calcium-activated potassium (BK) channels in spines from layer 5 PNs. We find that BK channels are localized to dendrites and spines regardless of their size, but their activity can only be detected in spines with small head volumes ([≤] 0.09 {micro}m3), which reduces the amplitude of two-photon (2P) uncaging (u) excitatory postsynaptic potentials (EPSPs) recorded at the soma. In addition, we find that calcium signals in spines with small head volumes are significantly larger than those observed in spines with larger head volumes. In accordance with our experimental data, numerical simulations predict that synaptic inputs impinging onto spines with small head volumes generate voltage responses and calcium signals within the spine head itself that are significantly larger than those observed in spines with bigger head volumes, which are sufficient to activate spine BK channels. These results show that BK channels are selectively activated in small-headed spines, suggesting a new level of dendritic spine-mediated regulation of synaptic processing, integration, and plasticity in cortical PNs.

neuroscience↗

bioRxiv2021

The Rules of Pulsatile Neurostimulation

Electrical stimulation is a key tool in neuroscience, both in brain mapping studies and in many therapeutic applications such as cochlear, vestibular, and retinal neural implants. Due to safety considerations, stimulation is restricted to short biphasic pulses. Despite decades of research and development, neural implants lead to varying restoration of function in patients. In this study, we use computational modeling to provide an explanation for how pulsatile stimulation affects axonal channels and therefore leads to variability in restoration of neural responses. The phenomenological explanation is transformed into equations that predict induced firing rate as a function of pulse rate, pulse amplitude, and spontaneous firing rate. We show that these equations predict simulated responses to pulsatile stimulation with a variety of parameters as well as several features of experimentally recorded vestibular afferent responses to pulsatile stimulation. We then discuss the implications of these effects for improving clinical stimulation paradigms and electrical stimulation-based experiments.

neuroscience↗

bioRxiv2018

A spike timing-dependent plasticity rule for single, clustered and distributed dendritic spines

Spike-timing-dependent plasticity (STDP) has been extensively studied in cortical pyramidal neurons, however, the precise structural organization of excitatory inputs that supports STDP, as well as the structural, molecular and functional properties of dendritic spines during STDP remain unknown. Here we performed a spine STDP protocol using two-photon glutamate uncaging to mimic presynaptic glutamate release (pre) paired with somatically generated postsynaptic spikes (post). We found that the induction of STDP in single spines follows a classical Hebbian STDP rule, where pre-post pairings at timings that trigger LTP (t-LTP) produce shrinkage of the activated spine neck and a concomitant increase in its synaptic strength; and post-pre pairings that trigger LTD (t-LTD) decrease synaptic strength without affecting the activated spine shape. Furthermore, we tested whether the single spine-Hebbian STDP rule could be affected by the activation of neighboring (clustered) or distant (distributed) spines. Our results show that the induction of t-LTP in two clustered spines (<5 m apart) enhances LTP through a mechanism dependent on local spine calcium accumulation and actin polymerization-dependent neck shrinkage, whereas t-LTD was disrupted by the activation of two clustered spines but recovered when spines were separated by >40 m. These results indicate that synaptic cooperativity, induced by the co-activation of only two clustered spines, provides local dendritic depolarization and local calcium signals sufficient to disrupt t-LTD and extend the temporal window for the induction of t-LTP, leading to STDP only encompassing LTP.

neuroscience↗