Pan European Networks: Science & Technology
Keisuke Yonehara, DVM, PhD
DANDRITE – Danish Research Institute of
Nordic EMBL Partnership for Molecular Medicine
+45 (0)9350 email@example.com http://dandrite.au.dk/people/gr oup- leaders/keisuke-yonehara-group/
group is embedded in the Danish Research
Institute of Translational Neuroscience
(DANDRITE), Aarhus University, Denmark, and
empowered by the ERC Starting Grant ‘CIRCUITASSEMBLY’. The
DANDRITE is a Danish node of the Nordic EMBL Partnership for
Molecular Medicine. The goal of my group is to understand how
the specificity in synaptic connectivity between neuronal cell types
defines neuronal computation in adults, and to understand the
genetic mechanism of how those neuronal circuits are assembled
Stabilising the visual world
Our visual system can function well even when the image of the
visual world is moving quickly.Why can you enjoy the beautiful
scene from the window while you are on a fast-moving train
without moving your eyes? The answer to that question is to be
found in the fact that our visual system is able to both detect the
speed and direction of the global image motion subconsciously,
and move the eyes to fix the image on the retina. That function is
called the ‘optokinetic reflex’, which is mediated by types of
direction-selective cells in the retina and its downstream visual
pathways, as suggested by studies in model animals such as
mice and rabbits.
Direction selectivity in the retina
In the retina, direction selectivity first arises at the dendrites of
A key circuit feature that creates the
direction selectivity is a spatially asymmetric inhibitory input from
starburst amacrine cells, an inhibitory neuronal type, to direction-
selective cells. If starburst cells are genetically ablated, both
retinal direction selectivity and optokinetic reflex are gone, as
demonstrated in the mouse study. The circuit asymmetry is
established from the symmetric circuit state during the neonatal
period without the need for visual experience.
molecular pathways leading to its establishment remain unknown.
Defective cell type in congenital nystagmus
An atlas of cell type transcriptome, created by Professor Botond
Roska at the Friedrich Miescher Institute and the University of
Basel, Switzerland, indicated that the expression of the FRMD7
gene in mouse retinas is enriched in starburst cells.
of FRMD7 in humans has been known to cause idiopathic
congenital nystagmus, a neurological disease in which the
optokinetic reflex is severely disturbed and thus vision is restricted.
Individuals without a functional FRMD7 allele have involuntary
horizontal eye oscillations (nystagmus) and lack the optokinetic
reflex along the horizontal axis. In contrast, along the vertical axis,
no nystagmus can be observed, and the optokinetic reflex is
unaffected.While FRMD7 expression has been localised to the
retina and the vestibular system, the neuronal circuit dysfunction
responsible for the symptoms of the disease is unknown.
We found that the mutation of FRMD7 in mice leads to the
selective loss of their horizontal optokinetic reflex, as it does in
This is accompanied by the selective loss of horizontal
direction selectivity in retinal ganglion cells, and the transition
from asymmetric to symmetric inhibitory input to horizontal
direction-selective ganglion cells. Vertical direction selectivity is not
dependent on FRMD7. In mice and primates the retinal
expression of FRMD7 is restricted to starburst cells. Our findings
established FRMD7 as a member of a previously unidentified
molecular pathway that is necessary for breaking the symmetry of
the developmental state of a neuronal circuit.
Our findings are also consistent with a hypothesis that
dysfunction of FRMD7 in starburst cells causes, at least partly, a
symptom of congenital nystagmus. To my knowledge, this is the
first time that we can link a disease to a defect in
neurocomputation. Our work suggests that gene function and cell
types in visual motion circuits are well conserved between mice
and primates, which is critical when one studies human disease
using animal models. This is an exciting time for neurobiological
research on mice, with an ever-expanding list of imaging
techniques, molecular, viral and genetic tools, and individual cell
types to which we have experimental access.
1 Yonehara, K.
The first stage of cardinal direction selectivity is localized to
the dendrites of retinal ganglion cells.
79, 1078-1085 (2013).
2 Yonehara, K.
Spatially asymmetric reorganization of inhibition
establishes a motion-sensitive circuit.
469, 407-410 (2011).
3 Siegert, S.
Transcriptional code and disease map for adult retinal cell
15, 487-495, S1-2 (2012).
4 Yonehara, K.
Congenital Nystagmus Gene FRMD7 Is Necessary for
Establishing a Neuronal Circuit Asymmetry for Direction Selectivity.
The Danish Research Institute of Translational Neuroscience writes
about neurocomputation and how it can be linked to disease
THE HUMAN BRAIN