of the Max - MDC

Cellular Neurosciences
Helmut Kettenmann
Our goal is to understand the role of glial cells in physiology and pathology. We focus on questions as to how
neuronal activity is sensed by astrocytes, how astrocytes communicate among each other, and how they
feedback on neurons. A second focus addresses the expression of transmitter receptors in microglial cells and
how activation of these receptors influences microglial function. This is of particular interest within the context
of pathology and we are currently studying this question in stroke and gliomas. A third line of research addresses
the question as to how glioma cells interact with the intrinsic brain cells, specifically microglia and stem cells. We
are aiming to understand this interaction on a molecular level, in particular with the hope of identifying tools
which impair glioma invasion.
The central nervous system contains two major cell populations,
neurons and glial cells. The neurons are regarded as
the elements mediating the electrical activity in the brain.
As a consequence, neuroscience research of the past has
focused on this cell type. The functional role of glial cells is
not as obvious: while they were first described as cells providing
only structural support to neurons, a series of more
recent studies on glial cell function has attracted the attention
of the neuroscience community. It has become evident
that glial cells are essential for the proper functioning of
the brain. The different types of glial cells fulfil distinct
tasks. Oligodendrocytes are the myelin-forming cells of the
central nervous system and ensure a rapid signal conduction
in the white matter. The role of astrocytes is less well
defined; they provide guiding structures during development
and represent important elements for controlling the
composition of the extracellular space mediating signals
between the brain endothelium and the neuronal membrane.
They form intimate contact with synapses and neuronal
activity results in astrocyte responses. Microglial cells
are immuno-competent cells in the brain and their functional
role is best defined as the first responsive elements during
pathologic events. The present research program is
focused on three topics: (1) the role of astrocytes in information
processing (2) the response of microglial cells to
brain injury and (3) the interaction of gliomas with
microglia and stem cells.
Mechanisms of neuron-astrocyte interactions
This project aims to understand signaling mechanisms
between astrocytes and neurons. We recently have focussed
on two preparations, the barrel cortex and the medial
nucleus of the trapezoid body. The Calyx of Held is a giant
glutamatergic terminal contacting principal neurons in this
nucleus. It has been used as a model synapse to study
mechanisms of transmitter release and synaptic plasticity
since both, pre- and postsynaptic elements can be simultaneously
recorded using physiological techniques. We have
studied the morphological arrangements and the properties
of the astrocytes which are in close contact with the Calyx.
We use brain slices containing the medial nucleus of the
trapezoid body and have established simultaneous recordings
of neurons and astrocytes. We obtained evidence that
two types of astrocytes perceive the Calyx activity. One type
of astrocyte is characterized by a complex membrane current
pattern and these cells receive synaptic input mediated
by glutamate. The other type of astrocyte characterized by a
passive membrane current pattern exhibit currents which
are due to glutamate uptake. Ultrastructural inspection
revealed that both types of astrocytes are in direct contact
with both, the pre- and postsynaptic membrane. Moreover,
we could identify glial postsynaptic structures on the cell
with complex current pattern. One goal of this study is to
determine how astrocytes integrate synaptic input from
defined synapses (funded by a Schwerpunktprogramm of
the DFG).
The sensory input of the whiskers in rodents is represented
in the somatosensory cortex. Each whisker projects into a
defined cortical area, the barrel field. These areas are morphologically
delineated and can be recognized in acute
brain slices without additional staining. The barrel cortex is
a well established model for plasticity since removal of
whiskers results in changes of the barrel fields. After stimulation
in the cortical layer 4, the input to the barrel field, we
can record responses in astrocytes and in neurons by using
Ca 2+ imaging and patch-clamp recording. While the neuronal
activity spreads beyond barrel borders, the astrocyte activity
is restricted to the barrel field.
160 Function and Dysfunction of the Nervous System