Extrasynaptic Glutamate Receptor Activation as Cellular Bases for Dynamic Range Compression in Pyramidal Neurons

Abstract

Repetitive synaptic stimulation overcomes the ability of astrocytic processes to clear glutamate from the extracellular space, allowing some dendritic segments to become submerged in a pool of glutamate, for a brief period of time. This dynamic arrangement activates extrasynaptic NMDA receptors located on dendritic shafts. We used voltage-sensitive and calcium-sensitive dyes to probe dendritic function in this glutamate-rich location. An excess of glutamate in the extrasynaptic space was achieved either by repetitive synaptic stimulation or by glutamate iontophoresis onto the dendrites of pyramidal neurons. Two successive activations of synaptic inputs produced a typical NMDA spike, whereas five successive synaptic inputs produced characteristic plateau potentials, reminiscent of cortical UP states. While NMDA spikes were coupled with brief calcium transients highly restricted to the glutamate input site, the dendritic plateau potentials were accompanied by calcium influx along the entire dendritic branch. Once initiated, the glutamate-mediated dendritic plateau potentials could not be interrupted by negative voltage pulses. Activation of extrasynaptic NMDA receptors in cellular compartments void of spines is sufficient to initiate and support plateau potentials. The only requirement for sustained depolarizing events is a surplus of free glutamate near a group of extrasynaptic receptors. Highly non-linear dendritic spikes (plateau potentials) are summed in a highly sublinear fashion at the soma, revealing the cellular bases of signal compression in cortical circuits. Extrasynaptic NMDA receptors provide pyramidal neurons with a function analogous to a dynamic range compression in audio engineering. They limit or reduce the volume of “loud sounds” (i.e., strong glutamatergic inputs) and amplify “quiet sounds” (i.e., glutamatergic inputs that barely cross the dendritic threshold for local spike initiation). Our data also explain why consecutive cortical UP states have uniform amplitudes in a given neuron.

Organization, control and function of extrasynaptic NMDA receptors

“…Some studies have reported a role for non-synaptic NMDARs in various functions such as extrasynaptic inhibition [95], or dynamic range compression [96]. But, aside from presynaptic NMDARs [97,98], which are not addressed in this review, most studies have focused on the manifestations of extrasynaptic NMDAR activity such as tonic currents and SICs.…”

Contribution of extrasynapticN-methyl-d-aspartate and adenosine A1 receptors in the generation of dendritic glutamate-mediated plateau potentials

“…The mean peak amplitude of the dendritic Ca 2þ signal at the synaptic stimulation site (figure 1b, patch, Ca 2þ region of interest-ROI) was 11.2 + 0.7% (DF/F), in the same sample of eight cells. Dendritic Ca 2þ signals were tightly restricted to the synaptic stimulation site as previously shown [5,8]. The synaptically evoked dendritic NMDA spikes were challenged with a potent antagonist of NR2C and D subunits, PPDA (2 mM).…”

“…Receptor channels located outside the synaptic cleft may also contribute charge to dendritic spikes [5,[12][13][14]. Besides the afferent glutamatergic axons, glial processes may also release glutamate that contributes to the glutamate build up (glutamate threshold) required to bring a dendrite into an UP state, which in turn brings the cell body into an UP state [1,15].…”

“…More importantly, the existence of multiple locations within thin dendrites, where these regenerative events can take place, enhances the computational power of an individual neuron, because each dendrite or specialized dendritic segment can serve as an autonomous decision-making computational unit [3,4]. Two classes of dendritic regenerative potentials, N-methyl-D-aspartate (NMDA) spikes and plateau potentials, exhibit distinct electrical (somatic) and calcium (dendritic) waveforms [5]. NMDA spikes are predominantly subthreshold events at the cell body, while dendritic plateau potentials reach much larger depolarization amplitudes and drastically longer durations.…”

“…This study is based on the hypothesis that both dendritic events, NMDA spikes and glutamate-mediated plateau potentials, are driven by five critical processes: (i) synchronous activation of spatially segregated presynaptic glutamatergic terminals [16], (ii) failure of nearby glial processes to clear the bulk of extracellular glutamate [5,12,13], (iii) stimulation of extrasynaptic NR2C/D receptors on spine necks and dendritic shafts by spilled-over glutamate [12,13,17,18], (iv) glutamatedependent release of adenosine from either neurons or glia, or both [19,20], and (v) activation of adenosine-sensitive dendritic K þ current, which imposes negative feedback on the amplitude and duration of dendritic depolarizations. The aforementioned five processes (i-v) synergistically contribute to the generation of local dendritic regenerative events.…”