Diverse role of NMDA receptors for dendritic integration of neural dynamics

Abstract

Neurons, represented as a tree structure of morphology, have various distinguished branches of dendrites. Different types of synaptic receptors distributed over dendrites are responsible for receiving inputs from other neurons. NMDA receptors (NMDARs) are expressed as excitatory units, and play a key physiological role in synaptic function. Although NMDARs are widely expressed in most types of neurons, they play a different role in the cerebellar Purkinje cells (PCs). Utilizing a computational PC model with detailed dendritic morphology, we explored the role of NMDARs at different parts of dendritic branches and regions. We found somatic responses can switch from silent, to simple spikes and complex spikes, depending on specific dendritic branches. Detailed examination of the dendrites regarding their diameters and distance to soma revealed diverse response patterns, yet explain two firing modes, simple and complex spike. Taken together, these results suggest that NMDARs play an important role in controlling excitability sensitivity while taking into account the factor of dendritic properties. Given the complexity of neural morphology varying in cell types, our work suggests that the functional role of NMDARs is not stereotyped but highly interwoven with local properties of neuronal structure.

Fig 1. Diverse somatic responses depending on the dendritic location of NMDARs.

(A) Stimulating 10 different sites individually on a PC morphological dendritic field. S1–S10 are typical sites, from spiny to primary dendrites. (B) PC somatic responses triggered by each stimulation site with and without NMDARs. 1000 NMDAR synapses were concentrated around each simulation site. (C) Detailed somatic membrane potential traces at three representative sites. S4: increased simple spikes; S6: decreased simple spikes; S9: change of complex spikes. (D) Somatic response profiles with the increasing number of synapses stimulated.

Fig 2. Dendritic and somatic responses under the randomly distributed NMDARs.

(A) Response recorded at different locations. (Left) four recording sites: R1 (spiny), R2 (distal), R3 (proximal) dendrite, R4 (soma). 1000 synapses (red dots) randomly distributed on the PC. (Middle) Voltage responses recorded at four sites with and without NMDARs. (B) The distribution of peaks of voltage potential triggered in (A) with NMDARs installed. (C) Response profiles at four sites varied with the number of input synapses (50 to 1000) with and without NMDARs. (D) The profiles of EPSP and the phase plots of voltage change by NMDARs.

Fig 3. Regulating response at different parts of dendritic fields by NMDARs.

(A) Regional synaptic distribution and dendrite potential profile. (Left) Synapses (1000 red spots) distributed in four regions (parts A-D) respectively. Insets are triggered voltage traces at each recording site (S1–S3 and Soma). (Right) The corresponding distribution of peaks of voltage potential. (B) Voltage profiles at four sites varied with the number of input synapses. (C) The corresponding phase plots of voltage profiles with 1000 synapses.

Fig 4. PC somatic response profiles induced by low-frequency Poisson inputs at different parts of dendrites.

Simplex spikes are triggered in all parts, while complex spikes are shown in Part A, C, and D.

Fig 5. Somatic responses depending on the dendritic properties of diameter and distance to soma.

(A) (Left) Different dendrites selected in part D that have either similar diameters (blue) or distance to the soma (purple) referring to the dendrite D816. (Right) Illustrating the locations of each dendrite: eight dendrites with different distances to soma; six dendrites with different diameters. (B) PC somatic response decreased with the increasing distance of the dendrites stimulated. (Right) The inset of enlarged membrane potential responses starting at the time of onset stimulation. For illustration, voltages were cut off at 40 mV. (C) Similar to (B), but for the case of varying dendritic diameters.

Fig 6. PC response to combined PF and CF inputs.

(A) PC installed with 500 PF AMPA synapses stimulated at 5 Hz Poisson spikes and a CF with 500 AMPA+NMDA synaptic connects stimulated at 2 Hz. Four recording sites (R1, spiny; R2, smooth; R3, trunk dendrites; Soma). (B) Voltage response of dendrites (R1–R3) and the soma. Spike timings of SS (black) and CS (red) are indicated as ticks. (C) Voltage response profiles zoomed in at a period (gray box in (B)) from all dendrites, sorted by their diameters and distances to the soma (top), and (below) profiles of each of four sites (R1–R3 and soma). (D) Similar to C, but with the changing strength of NMDA at different ratios of NMDA/AMPA while AMPA is fixed.

Fig 7. PC response to combined PF and CF inputs with inhibition input.

(A-C) Similar to Fig 6, but with 200 inhibitory synapses distributed on spiny dendrites at 10 Hz Poisson spike stimulation. (D-F) Similar to (A-C) while inhibitory synapses are distributed on smooth dendrites.