Scientists Solve Mystery of Human Brain’s Chandelier Cells

A new study published in the journal Science reveals for the first time the birth timing and embryonic origin of elusive brain cells called chandelier cells, and traces the specific paths they take during early development into an area of the brain called the cerebral cortex (often referred to as gray matter).

This image shows how axons from a single chandelier cell, (colored red, in the mouse cortex align precisely with green-labeled axon initial segments from many local excitatory cells (Hiroki Taniguchi et al / Cold Spring Harbor Laboratory)

Chandelier cells are found in all mammals, and believed to be responsible for epilepsy as well as higher logic in humans. They were first noticed only 40 years ago, and in the intervening years frustratingly little has been learned about them, beyond the fact that they hang individually among great crowds of excitatory cells in the cerebral cortex called pyramidal neurons, and that their relatively short branches make contact with these excitatory cells – a single chandelier cell connects with as many as 500 pyramidal neurons.

After three years of painstaking work, the scientists have demonstrated that chandelier cells are born in a previously unrecognized portion of the embryonic brain, which they have named the Ventral Germinal Zone (VGZ).

“While they are far less numerous than the excitatory pyramidal cells all around them, chandelier cells play an indispensable role in balancing message flow and ultimately in determining the functional organization of excitatory neurons into meaningful groups,” explained study senior author Prof Josh Huang of the Cold Spring Harbor Laboratory, NY.

“This is all the more intriguing in the case of chandelier cells,” Prof Huang said, “because of their distinctive anatomy: one cell that can regulate the messages of 500 others in its vicinity is one that we need to know about if we want to understand how brain circuits work. Unlike other inhibitory cells, chandelier cells are known to connect with excitatory cells at one particular anatomical location, of great significance: a place called the axon initial segment (AIS) – the spot where a ‘broadcasting’ pyramidal cell generates its transmittable message. To be able to interdict 500 ‘broadcasters’ at this point renders a single chandelier cell a very important player in message propagation and coordination within its locality.”

Chandelier cells are born in a previously undiscovered brain area named by the team the Ventral Germinal Zone, indicated with an arrow, the arrow-heads point to immature chandelier cells migrating from the VGZ toward positions in the mouse cerebral cortex where they will synapse with excitatory cells (Hiroki Taniguchi et al / Cold Spring Harbor Laboratory)

Because of the strategic importance of such cells throughout the cortex, it has been a source of frustration to neuroscientists that these and other inhibitory cells have been difficult to classify. Prof Huang has pursued a strategy of following them from their places of birth in the emerging cortex.

Many inhibitory cells come from a large incubator area called the Medial Ganglionic Eminence (MGE). Until now, it was not known that most chandelier cells are not born there, and indeed do not emerge until after the MGE has disappeared. Only at this point does the much smaller VGZ form, providing a place where neural precursor cells specifically give rise to chandelier cells.

The team found that manufacture of a protein encoded by a gene called Nkx2.1 is among the signals marking the birth of a chandelier cell. The gene’s action, they found, is also necessary to make the cells.

Nkx2.1 is a transcription factor, whose expression has previously been linked to the birth of other inhibitory neuronal types. The team observes that it is the timing of Nkx2.1’s expression in certain precursors – following disappearance of the MGE and appearance of the VGZ – that enabled them to track the birth, specifically, of chandelier cells.

“In addition to being surprised to discover that chandelier cells are born ‘late’ – after other inhibitory cells, in a part of the cortex we didn’t know about,” Prof Huang said, “our second surprise is that once born, these cells take a very stereotyped route into the cortex and assume very specific positions, in three cortical layers. This leads us to postulate that other specific cortical cell types also have specific migration routes in development.”

“New discoveries about chandelier cells have implications for disease research, since it is known that the number and connective density of chandelier cells is diminished in schizophrenia. Associations of the same type have recently been made in epilepsy,” Prof Huang concluded.

_______

Bibliographic information: Hiroki Taniguchi et al. The Spatial and Temporal Origin of Chandelier Cells in Mouse Neocortex. Science, published online November 22, 2012; doi: 10.1126/science.1227622