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Stroke is a leading cause of disability, but no pharmacological therapy
is currently available for promoting recovery. The brain region adjacent
to stroke damage—the peri-infarct zone—is critical for rehabilitation,
as it shows heightened neuroplasticity, allowing sensorimotor functions
to re-map from damaged areas1 (http://www.nature.com/nature/journal/v468/n7321/full/nature09511.html#ref1), 2 (http://www.nature.com/nature/journal/v468/n7321/full/nature09511.html#ref2), 3 (http://www.nature.com/nature/journal/v468/n7321/full/nature09511.html#ref3).
Thus, understanding the neuronal properties constraining this
plasticity is important for the development of new treatments. Here we
show that after a stroke in mice, tonic neuronal inhibition is increased
in the peri-infarct zone. This increased tonic inhibition is mediated
by extrasynaptic GABAA receptors and is caused by an impairment in GABA (γ-aminobutyric acid) transporter (GAT-3/GAT-4) function. To counteract the heightened inhibition, we administered in vivo a benzodiazepine inverse agonist specific for α5-subunit-containing extrasynaptic GABAA
receptors at a delay after stroke. This treatment produced an early and
sustained recovery of motor function. Genetically lowering the number
of α5- or δ-subunit-containing GABAA
receptors responsible for tonic inhibition also proved beneficial for
recovery after stroke, consistent with the therapeutic potential of
diminishing extrasynaptic GABAA receptor function. Together,
our results identify new pharmacological targets and provide the
rationale for a novel strategy to promote recovery after stroke and
possibly other brain injuries.
Andrew N. Clarkson,
Ben S. Huang,
Sarah E. MacIsaac,
Istvan Mody
S. Thomas Carmichael | Stroke is a leading cause of disability, but no pharmacological therapy
is currently available for promoting recovery. The brain region adjacent
to stroke damage—the peri-infarct zone—is critical for rehabilitation,
as it shows heightened neuroplasticity, allowing sensorimotor functions
to re-map from damaged areas.
Thus, understanding the neuronal properties constraining this
plasticity is important for the development of new treatments. Here we
show that after a stroke in mice, tonic neuronal inhibition is increased
in the peri-infarct zone. This increased tonic inhibition is mediated
by extrasynaptic GABAA receptors and is caused by an impairment in GABA (γ-aminobutyric acid) transporter (GAT-3/GAT-4) function. To counteract the heightened inhibition, we administered in vivo a benzodiazepine inverse agonist specific for α5-subunit-containing extrasynaptic GABAA
receptors at a delay after stroke. This treatment produced an early and
sustained recovery of motor function. Genetically lowering the number
of α5- or δ-subunit-containing GABAA
receptors responsible for tonic inhibition also proved beneficial for
recovery after stroke, consistent with the therapeutic potential of
diminishing extrasynaptic GABAA receptor function. Together,
our results identify new pharmacological targets and provide the
rationale for a novel strategy to promote recovery after stroke and
possibly other brain injuries.
Wyeth MS, Zhang N, Mody I, Houser CR
Perisomatic inhibition from basket cells plays an important role in
regulating pyramidal cell output. Two major subclasses of CA1 basket
cells can be identified based on their expression of either
cholecystokinin (CCK) or parvalbumin. This study examined their fates in
the mouse pilocarpine model of temporal lobe epilepsy. Overall,
immunohistochemical labeling of GABAergic boutons in the pyramidal cell
layer of CA1 was preserved in the mouse model. However, CCK-labeled
boutons in this layer were chronically reduced, whereas
parvalbumin-containing boutons were conserved. Immunohistochemistry for
cannabinoid receptor 1 (CB(1)), another marker for CCK-containing basket
cells, also labeled fewer boutons in pilocarpine-treated mice. Hours
after status epilepticus, electron microscopy revealed dark degenerating
terminals in the pyramidal cell layer with lingering CCK and CB(1)
immunoreactivity. In mice with recurrent seizures, carbachol-induced
enhancement of spontaneous IPSCs (sIPSCs) originating from
CCK-containing basket cells was accordingly reduced in CA1 pyramidal
cells. By suppressing sIPSCs from CCK-expressing basket cells, a CB(1)
agonist reverted the stimulatory effects of carbachol in naive mice to
levels comparable with those observed in cells from epileptic mice. The
agatoxin-sensitive component of CA1 pyramidal cell sIPSCs from
parvalbumin-containing interneurons was increased in pilocarpine-treated
mice, and miniature IPSCs were reduced, paralleling the decrease in
CCK-labeled terminals. Altogether, the findings are consistent with
selective reduction in perisomatic CA1 pyramidal cell innervation from
CCK-expressing basket cells in mice with spontaneous seizures and a
greater reliance on persisting parvalbumin innervation. This
differential alteration in inhibition may contribute to the
vulnerability of the network to seizure activity.
Santhakumar V, Jones RT, Mody I.
Striatal neurons are known to express GABA(A) receptor subunits that
underlie both phasic and tonic inhibition. Striatal projection neurons,
or medium spiny neurons (MSNs), are divided into two classes: MSNs
containing the dopamine D1 receptor (D1-MSNs) form the direct pathway to
the substantia nigra and facilitate movement while MSNs expressing the
dopamine D2 receptor (D2-MSNs) form the pallidal pathway that inhibits
movement. Consequently, modulating inhibition in distinct classes of
MSNs will differentially impact downstream network activity and motor
behavior. Given the powerful role of extrasynaptic inhibition in
controlling neuronal excitability, we examined the nature of striatal
tonic inhibition and its potential role in preventing excitotoxicity.
Consistent with earlier studies in young (P16-P25) mice, tonic GABA
currents in D2-MSNs were larger than in D1-MSNs. However, with age
(>P30 mice) the tonic GABA currents increased in D1-MSNs but
decreased in D2-MSNs. These data demonstrate a developmental switch in
the MSN subtype expressing larger tonic GABA currents. Compared to
wild-type, MSNs from adult mice lacking the GABA(A)R delta subunit
(Gabrd(-/-) mice) had both decreased tonic GABA currents and reduced
survival following an in vitro excitotoxic challenge with quinolinic
acid. Furthermore, muscimol-induced tonic GABA currents were accompanied
by reduced acute swelling of striatal neurons after exposure to NMDA in
WT mice but not in Gabrd(-/-) mice. Our data are consistent with a role
for tonic inhibition mediated by GABA(A)R delta subunits in
neuroprotection against excitotoxic insults in the adult striatum.
Copyright 2010 IBRO. All rights reserved.
Farshchi S, Pesterev A, Nuyujukian P, Guenterberg E, Mody I, Judy JW.
To create a wireless neural recording system that can benefit from the
continuous advancements being made in embedded microcontroller and
communications technologies, an embedded-system-based architecture for
wireless neural recording has been designed, fabricated, and tested. The
system consists of commercial-off-the-shelf wireless-enabled processor
modules (motes) for communicating the neural signals, and a back-end
database server and client application for archiving and browsing the
neural signals. A neural-signal-acquisition application has been
developed to enable the mote to either acquire neural signals at a rate
of 4000 12-bit samples per second, or detect and transmit spike heights
and widths sampled at a rate of 16670 12-bit samples per second on a
single channel. The motes acquire neural signals via a custom low-noise
neural-signal amplifier with adjustable gain and high-pass corner
frequency that has been designed, and fabricated in a 1.5-microm CMOS
process. In addition to browsing acquired neural data, the client
application enables the user to remotely toggle modes of operation
(real-time or spike-only), as well as amplifier gain and high-pass
corner frequency.
Mann EO, Mody I.
Gamma-frequency oscillations depend on phasic synaptic GABA(A) receptor
(GABA(A)R)-mediated inhibition to synchronize spike timing. The
spillover of synaptically released GABA can also activate extrasynaptic
GABA(A)Rs, and such tonic inhibition may also contribute to modulating
network dynamics. In many neuronal cell types, tonic inhibition is
mediated by delta subunit-containing GABA(A)Rs. We found that the
frequency of in vitro cholinergically induced gamma oscillations in the
mouse hippocampal CA3 region was increased by the activation of NMDA
receptors (NMDARs) on interneurons. The NMDAR-dependent increase of
gamma oscillation frequency was counteracted by the tonic inhibition of
the interneurons mediated by delta subunit-containing GABA(A)Rs.
Recordings of synaptic currents during gamma activity revealed that
NMDAR-mediated increases in oscillation frequency correlated with a
progressive synchronization of phasic excitation and inhibition in the
network. Thus, the balance between tonic excitation and tonic inhibition
of interneurons may modulate gamma frequency by shaping interneuronal
synchronization.