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LINKING NEUROCOMPUTATION

AND DISEASE

www.paneuropeannetworks.com

Pan European Networks: Science & Technology

19

207

PROFILE

Keisuke Yonehara, DVM, PhD

Group Leader

DANDRITE – Danish Research Institute of

Translational Neuroscience

Nordic EMBL Partnership for Molecular Medicine

Aarhus University

+45 (0)9350 8084

kyon@dandrite.au.dk http://dandrite.au.dk/people/gr oup- leaders/keisuke-yonehara-group/

MY

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

during development.

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

direction-selective cells.

1

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.

2

However, the

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.

3

The mutation

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

humans.

4

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.

References

1 Yonehara, K.

et al.

The first stage of cardinal direction selectivity is localized to

the dendrites of retinal ganglion cells.

Neuron

79, 1078-1085 (2013).

2 Yonehara, K.

et al.

Spatially asymmetric reorganization of inhibition

establishes a motion-sensitive circuit.

Nature

469, 407-410 (2011).

3 Siegert, S.

et al.

Transcriptional code and disease map for adult retinal cell

types.

Nat. Neurosci.

15, 487-495, S1-2 (2012).

4 Yonehara, K.

et al.

Congenital Nystagmus Gene FRMD7 Is Necessary for

Establishing a Neuronal Circuit Asymmetry for Direction Selectivity.

Neuron

89,

177-193 (2016).

The Danish Research Institute of Translational Neuroscience writes

about neurocomputation and how it can be linked to disease

THE HUMAN BRAIN