Parvalbumin in most gamma-aminobutyric acid-containing neurons of the rat cerebral cortex

gamma-Aminobutyric acid (GABA) is one of the major inhibitory neurotransmitters in the central nervous system. In the cerebral cortex, GABA-containing cells represent a subpopulation of interneurons. With semithin frozen sections, it is possible to demonstrate that most GABA neurons in the rat somatosensory cortex contain the calcium-binding protein parvalbumin and that parvalbumin is found virtually only in GABA neurons. Parvalbumin seems to influence the electrical properties and enzymatic machinery to modulate neuronal excitability and activity. The specific role of parvalbumin in GABA-containing cortical cells may be related to controlling the effectiveness of their inhibitory action.     

Maternal oxytocin triggers a transient inhibitory switch in GABA signaling in the fetal brain during delivery

We report a signaling mechanism in rats between mother and fetus aimed at preparing fetal neurons for delivery. In immature neurons, gamma-aminobutyric acid (GABA) is the primary excitatory neurotransmitter. We found that, shortly before delivery, there is a transient reduction in the intracellular chloride concentration and an excitatory-to-inhibitory switch of GABA actions. These events were triggered by oxytocin, an essential maternal hormone for labor. In vivo administration of an oxytocin receptor antagonist before delivery prevented the switch of GABA actions in fetal neurons and aggravated the severity of anoxic episodes. Thus, maternal oxytocin inhibits fetal neurons and increases their resistance to insults during delivery.     

Control of excitatory and inhibitory synapse formation by neuroligins

The normal function of neural networks depends on a delicate balance between excitatory and inhibitory synaptic inputs. Synapse formation is thought to be regulated by bidirectional signaling between pre- and postsynaptic cells. We demonstrate that members of the Neuroligin family promote postsynaptic differentiation in cultured rat hippocampal neurons. Down-regulation of neuroligin isoform expression by RNA interference results in a loss of excitatory and inhibitory synapses. Electrophysiological analysis revealed a predominant reduction of inhibitory synaptic function. Thus, neuroligins control the formation and functional balance of excitatory and inhibitory synapses in hippocampal neurons.     

Sequential interplay of nicotinic and GABAergic signaling guides neuronal development

GABA (gamma-aminobutyric acid), the major inhibitory transmitter in the brain, goes through a transitory phase of excitation during development. The excitatory phase promotes neuronal growth and integration into circuits. We show here that spontaneous nicotinic cholinergic activity is responsible for terminating GABAergic excitation and initiating inhibition. It does so by changing chloride transporter levels, shifting the driving force on GABA-induced currents. The timing of the transition is critical, because the two phases of GABAergic signaling provide contrasting developmental instructions. Synergistic with nicotinic excitation, GABAergic inhibition constrains neuronal morphology and innervation. The results reveal a multitiered activity-dependent strategy controlling neuronal development.     

Inhibitory plasticity balances excitation and inhibition in sensory pathways and memory networks

Cortical neurons receive balanced excitatory and inhibitory synaptic currents. Such a balance could be established and maintained in an experience-dependent manner by synaptic plasticity at inhibitory synapses. We show that this mechanism provides an explanation for the sparse firing patterns observed in response to natural stimuli and fits well with a recently observed interaction of excitatory and inhibitory receptive field plasticity. The introduction of inhibitory plasticity in suitable recurrent networks provides a homeostatic mechanism that leads to asynchronous irregular network states. Further, it can accommodate synaptic memories with activity patterns that become indiscernible from the background state but can be reactivated by external stimuli. Our results suggest an essential role of inhibitory plasticity in the formation and maintenance of functional cortical circuitry.     

Specialized inhibitory synaptic actions between nearby neocortical pyramidal neurons

We found that, in the mouse visual cortex, action potentials generated in a single layer-2/3 pyramidal (excitatory) neuron can reliably evoke large, constant-latency inhibitory postsynaptic currents in other nearby pyramidal cells. This effect is mediated by axo-axonic ionotropic glutamate receptor-mediated excitation of the nerve terminals of inhibitory interneurons, which connect to the target pyramidal cells. Therefore, individual cortical excitatory neurons can generate inhibition independently from the somatic firing of inhibitory interneurons.     

Long-range-projecting GABAergic neurons modulate inhibition in hippocampus and entorhinal cortex

The hippocampus and entorhinal cortex play a pivotal role in spatial learning and memory. The two forebrain regions are highly interconnected via excitatory pathways. Using optogenetic tools, we identified and characterized long-range γ-aminobutyric acid-releasing (GABAergic) neurons that provide a bidirectional hippocampal-entorhinal inhibitory connectivity and preferentially target GABAergic interneurons. Activation of long-range GABAergic axons enhances sub- and suprathreshold rhythmic theta activity of postsynaptic neurons in the target areas.     

Delayed transneuronal death of substantia nigra neurons prevented by gamma-aminobutyric acid agonist

In an investigation of the mechanism by which brain lesions result in delayed degeneration of neurons remote from the site of injury, neurons within the caudate nucleus of rats were destroyed by local injection of the excitotoxin ibotenic acid. Treatment resulted in the rapid degeneration of the striatonigral pathway including projections containing the inhibitory neurotransmitter gamma-aminobutyric acid (GABA) and delayed transneuronal death of neurons in the substantia nigra pars reticulata. The distribution of nigral cell loss corresponded to the loss of GABAergic terminals. Neuronal death was prevented by long-term intraventricular infusion of the GABA agonist muscimol. Delayed transneuronal degeneration may be produced by neuronal disinhibition consequent to loss of inhibitory inputs. Replacement of inhibitory transmitters by suitable drugs may prevent some forms of delayed neuronal death.     

Channel-mediated tonic GABA release from glia

Synaptic inhibition is based on both tonic and phasic release of the inhibitory transmitter γ-aminobutyric acid (GABA). Although phasic GABA release arises from Ca(2+)-dependent exocytosis from neurons, the mechanism of tonic GABA release is unclear. Here we report that tonic inhibition in the cerebellum is due to GABA being released from glial cells by permeation through the Bestrophin 1 (Best1) anion channel. We demonstrate that GABA directly permeates through Best1 to yield GABA release and that tonic inhibition is eliminated by silencing of Best1. Glial cells express both GABA and Best1, and selective expression of Best1 in glial cells, after preventing general expression of Best1, fully rescues tonic inhibition. Our results identify a molecular mechanism for tonic inhibition and establish a role for interactions between glia and neurons in mediating tonic inhibition.     

Identified sources and targets of slow inhibition in the neocortex

There are two types of inhibitory postsynaptic potentials in the cerebral cortex. Fast inhibition is mediated by ionotropic gamma-aminobutyric acid type A (GABA(A)) receptors, and slow inhibition is due to metabotropic GABA(B) receptors. Several neuron classes elicit inhibitory postsynaptic potentials through GABA(A) receptors, but possible distinct sources of slow inhibition remain unknown. We identified a class of GABAergic interneurons, the neurogliaform cells, that, in contrast to other GABA-releasing cells, elicited combined GABA(A) and GABA(B) receptor-mediated responses with single action potentials and that predominantly targeted the dendritic spines of pyramidal neurons. Slow inhibition evoked by a distinct interneuron in spatially restricted postsynaptic compartments could locally and selectively modulate cortical excitability.     

Rapid rewiring of arcuate nucleus feeding circuits by leptin

The fat-derived hormone leptin regulates energy balance in part by modulating the activity of neuropeptide Y and proopiomelanocortin neurons in the hypothalamic arcuate nucleus. To study the intrinsic activity of these neurons and their responses to leptin, we generated mice that express distinct green fluorescent proteins in these two neuronal types. Leptin-deficient (ob/ob) mice differed from wild-type mice in the numbers of excitatory and inhibitory synapses and postsynaptic currents onto neuropeptide Y and proopiomelanocortin neurons. When leptin was delivered systemically to ob/ob mice, the synaptic density rapidly normalized, an effect detectable within 6 hours, several hours before leptin's effect on food intake. These data suggest that leptin-mediated plasticity in the ob/ob hypothalamus may underlie some of the hormone's behavioral effects.     

Decreased hippocampal inhibition and a selective loss of interneurons in experimental epilepsy

The occurrence of seizure activity in human temporal lobe epilepsy or status epilepticus is often associated with a characteristic pattern of cell loss in the hippocampus. An experimental model that replicates this pattern of damage in normal animals by electrical stimulation of the afferent pathway to the hippocampus was developed to study changes in structure and function that occur as a result of repetitive seizures. Hippocampal granule cell seizure activity caused a persistent loss of recurrent inhibition and irreversibly damaged adjacent interneurons. Immunocytochemical staining revealed unexpectedly that gamma-aminobutyric acid (GABA)-containing neurons, thought to mediate inhibition in this region and predicted to be damaged by seizures, had survived. In contrast, there was a nearly complete loss of adjacent somatostatin-containing interneurons and mossy cells that may normally activate inhibitory neurons. These results suggest that the seizure-induced loss of a basket cell-activating system, rather than a loss of inhibitory basket cells themselves, may cause disinhibition and thereby play a role in the pathophysiology and pathology of the epileptic state.     

Clonal production and organization of inhibitory interneurons in the neocortex

The neocortex contains excitatory neurons and inhibitory interneurons. Clones of neocortical excitatory neurons originating from the same progenitor cell are spatially organized and contribute to the formation of functional microcircuits. In contrast, relatively little is known about the production and organization of neocortical inhibitory interneurons. We found that neocortical inhibitory interneurons were produced as spatially organized clonal units in the developing ventral telencephalon. Furthermore, clonally related interneurons did not randomly disperse but formed spatially isolated clusters in the neocortex. Individual clonal clusters consisting of interneurons expressing the same or distinct neurochemical markers exhibited clear vertical or horizontal organization. These results suggest that the lineage relationship plays a pivotal role in the organization of inhibitory interneurons in the neocortex.     

Acetylcholine and GABA mediate opposing actions on neuronal chloride channels in crayfish

A central principle of neural integration is that excitatory and inhibitory neurotransmitters effect the opening of distinct classes of membrane ionic channels and that integration consists of the summation of the opposing ionic currents on the postsynaptic membrane. In tangential cells of crayfish optic lobes, a hyperpolarizing, biphasic synaptic potential is produced by the concurrent action of acetylcholine and gamma aminobutyric acid (GABA). Acetylcholine hyperpolarizes the cell and increases chlorine conductance. GABA depolarizes the cell by closing some of the same chloride channels. Therefore, in this case integration is achieved by the antagonistic actions of two transmitters on the same ionic channel.     

Leonurine protects ischemia-induced brain injury via modulating SOD,MDA and GABA levels

The present study was designed to investigate the protective effects of leonurine, a compound purified from Herba Leonuri that is active on ischemic rat behavior and cortical neurons, and explore the underlying mechanism. The general rat activity, cortical neuron morphology, superoxide dismutase (SOD), malondialdehyde (MDA), g-aminobutyric acid (GABA) and glutamate decarboxylase 67 (GAD67) levels were measured. We found leonurine significantly improve the general activity of rats in an open-field test, which was associated with attenuated neuronal damage induced by ischemia. Moreover, serum SOD activity was significantly greater, MDA level lower in the leonurine group as compared with ischemia group. In addition, GABA content in the cerebral cortex was significantly greater in high-dose leonurine group. Correspondingly, GAD67 protein level coincided with the GABA level. Taken together, our results demonstrated that leonurine attenuated brain injury during ischemia via antioxidative and anti-excitotoxicity effects by targeting GABA and leonurine might become a useful adjuvant neuroprotective agent.     

Functional coupling of gamma-aminobutyric acid receptors to chloride channels in brain membranes

gamma-Aminobutyric acid (GABA), the major inhibitory neurotransmitter in mammalian brain, is believed to act by increasing membrane conductance of chloride ions. In this study it was found that GABA agonists increased the uptake of chloride-36 by cell-free membrane preparations from mouse brain. This influx was rapid (less than 5 seconds), and 13 micromolar GABA produced a half-maximal effect. The GABA antagonists (bicuculline and picrotoxin) blocked the effect of GABA, whereas pentobarbital enhanced the action. This may be the first demonstration of functional coupling among GABA and barbiturate receptors and chloride channels in isolated membranes. The technique should facilitate biochemical and pharmacological studies of GABA receptor-effector coupling.     

Brain glutamate decarboxylase cloned in lambda gt-11: fusion protein produces gamma-aminobutyric acid

Glutamate decarboxylase (GAD; E.C. 4.1.1.15) converts glutamate to gamma-aminobutyric acid (GABA), the major inhibitory neurotransmitter in the vertebrate central nervous system. This report describes the isolation of a GAD complementary DNA clone by immunological screening of a lambda gt-11 brain complementary DNA expression library. The fusion protein produced by this clone catalyzes the conversion of glutamate to GABA and carbon dioxide, confirming its identity as GAD. Antibodies to beta-galactosidase remove GAD enzymatic activity from solution, showing that this activity is associated with the fusion protein. In immunoblotting experiments all three available antisera to GAD reacted with the fusion polypeptide and with two major polypeptides (molecular size, 60,000 and 66,000 daltons) in brain extracts.     

Newly identified 'glutamate interneurons' and their role in locomotion in the lamprey spinal cord

A new class of excitatory premotor interneurons that are important in the generation of locomotion in the lamprey has now been described. In the isolated spinal cord, these neurons act simultaneously with their postsynaptic motoneurons during fictive swimming. They are small and numerous, and they monosynaptically excite both motoneurons and inhibitory premotor interneurons. The excitatory postsynaptic potentials are depressed by an antagonist of excitatory amino acids. These interneurons receive reticulospinal input from the brain stem and polysynaptic input form skin afferents. A model of the network underlying locomotion based on the synaptic interactions of these neurons can now be proposed for the lamprey.     

Substance P: a putative sensory transmitter in mammalian autonomic ganglia

Repetitive presynaptic stimulation elicited slow membrane depolarization in neurons of inferior mesenteric ganglia from guinea pigs. This response was not blocked by cholinergic antagonists but was specifically and reversibly inhibited by a substance P analog, (D-Pro2, D-Phe7, D-Trp9)-substance P, which also depressed the depolarization induced by exogenously applied substance P. The atropine-sensitive slow excitatory and slow inhibitory postsynaptic potentials evoked in neurons of rabbit superior cervical ganglia were not affected by the substance P analog. These and previous results provide strong support for the hypothesis that substance P or a closely related peptide is the transmitter mediating the slow depolarization. The latter may represent a sensory input from the gastrointestinal tract to neurons of the prevertebral ganglia.     

Command neurons in Pleurobranchaea receive synaptic feedback from the motor network they excite

Command neurons that cause rhythmic feeding behavior in the marine mollusc Pleurobranchaea californica have been identified in the cerebropleural ganglion (brain). Intracellular stimulation of single command neurons in isolated nervous systems, semi-intact prepartions, and restrained whole animals causes the same rhythmic motor output pattern as occurs during feeding. During this motor output pattern, action potentials recorded intracellularly from the command neurons occur in cyclic bursts that are phase-locked with the feeding rhythm. This modulation results from repetitive, alternating bursts of excitatory and inhibitory postsynaptic potentials, which are caused at least in part by synaptic feedback to the command neurons from identified classes of neurons in the feeding network. Central feedback to command neurons from the motor network they excite provides a possible general physiological mechanism for the sustained oscillation of neural networks controlling cyclic behavior.