Form and function of the M4 cell, an intrinsically photosensitive retinal ganglion cell type contributing to geniculocortical vision

J Neurosci. 2012 Sep 26;32(39):13608-20. doi: 10.1523/JNEUROSCI.1422-12.2012.


The photopigment melanopsin confers photosensitivity upon a minority of retinal output neurons. These intrinsically photosensitive retinal ganglion cells (ipRGCs) are more diverse than once believed, comprising five morphologically distinct types, M1 through M5. Here, in mouse retina, we provide the first in-depth characterization of M4 cells, including their structure, function, and central projections. M4 cells apparently correspond to ON α cells of earlier reports, and are easily distinguished from other ipRGCs by their very large somata. Their dendritic arbors are more radiate and highly branched than those of M1, M2, or M3 cells. The melanopsin-based intrinsic photocurrents of M4 cells are smaller than those of M1 and M2 cells, presumably because melanopsin is more weakly expressed; we can detect it immunohistochemically only with strong amplification. Like M2 cells, M4 cells exhibit robust, sustained, synaptically driven ON responses and dendritic stratification in the ON sublamina of the inner plexiform layer. However, their stratification patterns are subtly different, with M4 dendrites positioned just distal to those of M2 cells and just proximal to the ON cholinergic band. M4 receptive fields are large, with an ON center, antagonistic OFF surround and nonlinear spatial summation. Their synaptically driven photoresponses lack direction selectivity and show higher ultraviolet sensitivity in the ventral retina than in the dorsal retina, echoing the topographic gradient in S- and M-cone opsin expression. M4 cells are readily labeled by retrograde transport from the dorsal lateral geniculate nucleus and thus likely contribute to the pattern vision that persists in mice lacking functional rods and cones.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Actins / genetics
  • Actins / metabolism
  • Animals
  • Cholera Toxin / metabolism
  • Choline O-Acetyltransferase / metabolism
  • Dendrites / metabolism
  • Dendrites / ultrastructure
  • Electroretinography
  • Female
  • Geniculate Bodies / physiology*
  • Green Fluorescent Proteins / genetics
  • Light
  • Male
  • Membrane Potentials / drug effects
  • Membrane Potentials / genetics
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Patch-Clamp Techniques
  • Photic Stimulation / methods
  • Retina
  • Retinal Ganglion Cells / classification*
  • Retinal Ganglion Cells / physiology*
  • Retinal Ganglion Cells / ultrastructure
  • Rod Opsins / genetics
  • Rod Opsins / metabolism*
  • Visual Cortex / physiology*
  • Visual Fields / drug effects
  • Visual Fields / genetics
  • Visual Pathways / physiology
  • beta-Galactosidase / genetics
  • beta-Galactosidase / metabolism


  • Actins
  • Rod Opsins
  • enhanced green fluorescent protein
  • melanopsin
  • Green Fluorescent Proteins
  • Cholera Toxin
  • Choline O-Acetyltransferase
  • beta-Galactosidase