Date of Completion

8-26-2014

Embargo Period

8-18-2024

Major Advisor

Srdjan Antic

Associate Advisor

Shigeyuki Kuwada

Associate Advisor

Richard Mains

Associate Advisor

Oliver Douglas

Field of Study

Biomedical Science

Degree

Doctor of Philosophy

Open Access

Open Access

Abstract

Basal dendrites are a major target of excitatory synaptic inputs in cortical pyramidal neurons. Due to their close proximity to the soma, basal dendrites strongly influence the neuronal output via generation of dendritic regenerative potentials (spikes). Dendritic spikes are generated by synchronous activation of spatially segregated glutamatergic terminals. It was recently postulated that astrocytes actively support dendritic spikes by either ceasing the glutamate uptake or by releasing glutamate and adenosine in the extrasynaptic space. The pool of extrasynaptic glutamate receptors exposed to spillover glutamate is dominated by NR2B, NR2C and NR2D subtypes of the NMDA receptors.

Using whole-cell patch-clamp recordings, calcium imaging and pharmacological agents, we found that both NR2B and NR2C/D receptors significantly contribute to the amplitude of synaptically-evoked NMDA spikes. Dendritic calcium signal associated with glutamate-mediated plateau potentials suffered significant shortening upon application of the NR2C/D receptor antagonist PPDA, suggesting that NR2C/D NMDA receptors serve to regulate the duration of calcium influx during dendritic spiking. In contrast to NR2C/D receptors, the A1 adenosine receptors act to abbreviate dendritic and somatic signals via the activation of dendritic slow outward rectifying K+ current, which was found to be insensitive to 4-AP but sensitive to TEA.

We found NMDA spikes and plateau potentials in 4 classes of spiny forebrain neurons including medium spiny neurons of neostriatum, spiny neurons of amygdala, cortical layer 4 stellate neurons and cortical layer 5 pyramidal neurons. All 4 neuron types have previously been demonstrated to engage in UP and DOWN states during non-REM slow-wave sleep. We propose that the biophysical properties of spiny dendrites allow neurons to quickly attune to the ongoing network activity, as well as secure the stable amplitudes of successive UP states. Furthermore, we hypothesized that neuronal UP states in vivo reflect the occurrence of dendritic plateau potentials. We propose that the somatic voltage waveform during a neuronal UP state is closely determined by dendritic plateau potentials. Finally, because the NR2B/C/D-containing NMDA receptors are mostly found outside the synaptic cleft, our data emphasize the role of glutamate “spillover” in the process of dendritic regenerative spikes and associated local calcium influx.

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