Focal Cortical Lesions Induce Bidirectional Changes in the Excitability of Fast Spiking and Non Fast Spiking Cortical Interneurons
Mittmann T (2014) Focal Cortical Lesions Induce Bidirectional Changes in the Excitability of Fast Spiking and Non Fast Spiking
Cortical Interneurons. PLoS ONE 9(10): e111105. doi:10.1371/journal.pone.0111105
Focal Cortical Lesions Induce Bidirectional Changes in the Excitability of Fast Spiking and Non Fast Spiking Cortical Interneurons
Barbara Imbrosci. 0
Angela Neitz. 0
Thomas Mittmann 0
Gennady Cymbalyuk, Georgia State University, United States of America
0 Institute of Physiology, University Medical Center of the Johannes-Gutenberg University Mainz , Mainz , Germany
A physiological brain function requires neuronal networks to operate within a well-defined range of activity. Indeed, alterations in neuronal excitability have been associated with several pathological conditions, ranging from epilepsy to neuropsychiatric disorders. Changes in inhibitory transmission are known to play a key role in the development of hyperexcitability. However it is largely unknown whether specific interneuronal subpopulations contribute differentially to such pathological condition. In the present study we investigated functional alterations of inhibitory interneurons embedded in a hyperexcitable cortical circuit at the border of chronically induced focal lesions in mouse visual cortex. Interestingly, we found opposite alterations in the excitability of non fast-spiking (Non Fs) and fast-spiking (Fs) interneurons in acute cortical slices from injured animals. Non Fs interneurons displayed a depolarized membrane potential and a higher frequency of spontaneous excitatory postsynaptic currents (sEPSCs). In contrast, Fs interneurons showed a reduced sEPSCs amplitude. The observed downscaling of excitatory synapses targeting Fs interneurons may prevent the recruitment of this specific population of interneurons to the hyperexcitable network. This mechanism is likely to seriously affect neuronal network function and to exacerbate hyperexcitability but it may be important to protect this particular vulnerable population of GABAegic neurons from excitotoxicity.
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Funding: This work is supported by the German Research Foundation (DFG, CRC 1080, TP-A7) to T.M. and by a MAIFOR grant to B.I. The funders had no role in
study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Competing Interests: The authors have declared that no competing interests exist.
. These authors contributed equally to this work.
Focal cortical injuries are often followed by perturbations in the
excitability of the surviving neuronal networks. It has been
assumed that the development of this abnormal neuronal activity
is the result of an imbalance between excitation and inhibition,
where changes in inhibition are believed to play the most
important role [1]. An impaired inhibitory transmission has been
reported in several animal models of both traumatic and ischemic
brain injury [2,3]. Functionally, the impaired GABAergic
transmission has been attributed to a reduced release of GABA from
presynaptic terminals [4], to changes in the expression of GABA
receptors [5] and to a dysfunction in Cl2 transport [6]. Recent
evidence also suggested changes in tonic inhibition, with potential
deleterious consequences on neuronal network function and
plasticity [7,8]. A significant reduction in the axonal length and
in the number of synaptic contacts formed by fast-spiking
interneurons has also been reported following brain lesions [9].
Despite this wealth of knowledge, most reports primarily focused
on the output synapses of GABAergic neurons. Therefore,
studying the impact of the loss of a cortical area on the excitability
of GABAergic cells remains the missing piece of the puzzle for a
comprehensive understanding of the cellular mechanisms
underlying cortical network dysfunction and hyperexcitability
postinjury. In the present study we employed an ex vivo-in vitro model
of laser-lesions in mouse visual cortex to study the functional
properties of GABAergic interneurons in the cortical network
adjacent to the lesion. The injured cortex showed clear signs of
hyperexcitability in the first week post-lesion as reveled by a robust
increase in the spontaneous neuronal firing from multi-electrode
array (MEA) extracellular recordings. Interestingly, we disclosed
that the modulation in the excitability of GABAergic cells was cell
type-specific. In particular, we observed an elevated excitability in
a large subpopulation of GABAergic cells that we identified, based
on specific firing properties, as non fast-spiking (Non Fs)
interneurons. In contrast, fast-spiking (Fs), parvalbumin-expressing
interneurons displayed a reduction in the strength of their
excitatory drive and therefore tended to be hypoexcitable. We
hypothesize that the specific functional alterations observed at Fs
interneurons may represent a mechanism of synaptic downscaling
engaged to protect this particular vulnerable population of
GABAegic cells from excitotoxicity (...truncated)