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Results for “inhibitory interneurons”

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At least 19 recordsLinked to original sources

PubMed2001

A hebbian form of long-term potentiation dependent on mGluR1a in hippocampal inhibitory interneurons.

Hippocampal inhibitory interneurons play important roles in controlling the excitability and synchronization of pyramidal cells, but whether they express long-term synaptic plasticity that contributes to hippocampal network function remains uncertain. We found that pairing postsynaptic depolarization with theta-burst stimulation induced long-term potentiation (LTP) of putative single-fiber excitatory postsynaptic currents in interneurons. Either postsynaptic depolarization or theta-burst stimulation alone failed to induce LTP. LTP was expressed as a decrease in failure rates and an increase in excitatory postsynaptic current amplitude, independent of N-methyl-d-aspartate receptors, and dependent on metabotropic glutamate receptors subtype 1a. LTP was induced specifically in interneurons in stratum oriens and not in interneurons of stratum radiatum/lacunosum-moleculare. Thus, excitatory synapses onto specific subtypes of inhibitory interneurons express a new form of hebbian LTP that will contribute to hippocampal network plasticity.

Animals↗

PubMed1994

Synchronous bursting in a subset of interneurons inhibitory to the goldfish Mauthner cell: synaptic mediation and plasticity.

1. Presynaptic activity in the inhibitory network impinging on the Mauthner (M-) cell was investigated in the goldfish medulla in vivo using extra- and intracellular recordings. The inhibitory presynaptic volley elicited by stimulation of the contralateral vestibular nerve consisted of multiple successive peaks at high frequency (up to 1,000 Hz). Less pronounced multicomponent responses were recorded after antidromic activation of the M-cell. Such high-frequency "oscillatory" field potentials also occurred spontaneously. 2. In intracellular recordings, a subset of inhibitory interneurons showed evoked and spontaneous burst discharge. Burst action potentials were correlated with the peaks in the extracellular volley, suggesting that repetitive firing of these cells is synchronized. Nonbursting cells, on the other hand, fired single action potentials in response to vestibular stimuli and were not activated via the M-cell collateral network. 3. Bursting cells were determined morphologically to be part of the feedback inhibitory circuit. Their responses to stimulation of the contralateral vestibular nerve thus suggest the existence of a crossed excitatory pathway to these interneurons. 4. Vestibular-evoked excitatory postsynaptic potentials (EPSPs) in bursting interneurons had a short latency of 0.781 +/- 0.08 ms (mean +/- SD, n = 18) but reached threshold at 2.25 +/- 1 ms (n = 21). These characteristics are suggestive of a chemically mediated EPSP. Indeed, the evoked synchronous repetitive activity of these cells was prevented by superfusion with excitatory amino-acid receptor antagonists. 5. Bursting neurons showed several characteristics that differentiate them from nonbursting cells, including brief action potentials, plateau responses, and intense spontaneous subthreshold activity. 6. With extracellular recordings, tetanization of contralateral vestibular primary afferents evoked a long-lasting potentiation of oscillatory population responses in 11 of 27 cases. Furthermore in three experiments, the frequency of occurrence of spontaneous bursts was enhanced and a similar facilitation was detected at the intracellular level. 7. We conclude that a subset of interneurons in this inhibitory network is capable of repetitive discharges and that evoked as well as spontaneous firing in this population is synchronized. Although electrical coupling between interneurons may mediate synchronization and intrinsic membrane properties may promote burst activity, our data suggest strongly that repetitive firing requires chemically mediated transmission. Furthermore they indicate that the mechanisms underlying evoked as well as spontaneous bursting in this population show activity-dependent plasticity.

Animals↗

PubMed2002

Pre- and postsynaptic inhibition mediated by GABA(B) receptors in cerebellar inhibitory interneurons.

The inhibitory interneurons in the molecular layer of the cerebellar cortex form a complex network, interconnected by both chemical and electrotonic synapses. Previous work, using voltage optical imaging in an isolated cerebellum, has indicated that these interneurons also form presynaptic inhibitory interconnections. Here we examine the participation of GABA(B) receptors in the proposed presynaptic inhibition by recording from the molecular layer interneurons (MLI) in cerebellar slices. The GABA(B) agonist, baclofen, profoundly depressed synaptic transmission; a concentration of 10 microM decreased the frequency of spontaneous inhibitory synaptic potentials by 82 +/- 15% and of miniature synaptic potentials by 75 +/- 13%. In simultaneous recording from two synaptically interconnected MLIs, baclofen (10 microM) increased the failure rate of synaptic transmission by a factor of 3, confirming a presynaptic mechanism, most likely mediated by a decrease in calcium conductance. A postsynaptic effect of baclofen was also found; 10 microM decreased the spontaneous firing rate by 55 +/- 19% even in the presence of synaptic blockers. One hundred micromolar baclofen induced an averaged hyperpolarization of 6 +/- 2 mV or an averaged 7.8 +/- 3 pA net outward current that can account for the decrease in firing rate. The outward current reflects a reduction in a tonic Ca(2+) current, since it was abolished by blocking Ca(2+) currents and remained unchanged in the presence of Ba(2+). Application of the specific GABA(B) blocker, CGP 55845A (1 microM), not only reversed the effects of baclofen but also increased the spontaneous firing rate and synaptic activity when applied alone. Thus in slice preparations, GABA(B) receptors are tonically activated by endogenous GABA. The temporal role of GABA(B) receptors was tested using the paired-pulse paradigm. Recording from two synaptically interconnected MLIs showed a 3.5 times lower probability of release for the second stimulus. In the isolated cerebellar preparation, a robust depression of the second inhibitory response was observed. This depression was partially blocked by CGP 55845A (2 microM). We conclude that both the pre- and postsynaptic effects of baclofen are mediated by GABA(B) receptors that decrease Ca(2+) currents. These can serve a modulatory role as well as participating in shaping the temporal interactions between consecutive inputs.

Animals↗

PubMed2002

Jittery trains induced by synaptic-like currents in cerebellar inhibitory interneurons.

Cerebellar inhibitory interneurons respond to parallel fiber input with a characteristic train of action potentials. Here we show that the characteristics of these trains reflect the intrinsic properties of the interneurons. In in vitro cerebellar slices, the response of these neurons to synaptic-like current resembles their in vivo response to parallel fiber input-a train of action potentials characterized by a gradual increase in interspike interval and spike amplitude. A large variability in spike timing, or jitter, was observed, the last action potential emerging from a slow depolarizing wave that lasted beyond the synaptic current and was prevented by either TTX or membrane hyperpolarization. While response duration was weakly dependent on current intensity, the variability of the overall duration was closely related to the variability of the timing of the last action potential. Blocking the Ca(2+) currents or partial blockade of the delayed rectifier (TEA 2 mM) decreased the excitability, leading to a decrease in the duration and variability of the response and increasing its dependence on stimulus intensity. Increased duration and variability was observed in the presence of Cs(+) ions (5 mM) that blocked an h-like current. We conclude that a persistent Na(+) current governs the duration of the response, whereas the synaptic current and the spiking mechanism shape its pattern. The large variability between trials is due to the stochastic nature of the persistent Na(+) current. Thus unless precise timing is achieved by a network of interconnected neurons, these results vote against temporal coding as a player in the cerebellar computational processing.

Action Potentials↗

PubMed2003

Interneuron diversity series: inhibitory interneurons and network oscillations in vitro.

In vitro models of rhythms of cognitive relevance, such as gamma (30-80 Hz) and theta (5-12 Hz) rhythms in the hippocampus, demonstrate an absolute requirement for phasic inhibitory synaptic transmission. Such rhythms can occur transiently, of approximately 1 s duration, or persistently, lasting for many hours. In the latter case, stable patterns of interneuron output, and their postsynaptic consequences for pyramidal cell membrane potential, occur despite known constraints of synaptic habituation and potentiation. This review concentrates on recent in vitro evidence revealing a division of labour among different subclasses of interneurons with respect to the frequency of persistent rhythms, and the crucial dependence on gap-junction-mediated intercellular communication for the generation and maintenance of these rhythms.

Animals↗

PubMed2004

Immunohistochemical localization of cannabinoid CB1 receptor in inhibitory interneurons in the cerebellum.

Inhibitory interneurons terminating on Purkinje cell dendrites contribute to cannabinoid-mediated cerebellar plasticity, consistent with the intense expression of cannabinoid CB1 receptor protein in the cerebellar molecular layer. CB1 labelling in the molecular layer has been attributed to parallel fibers originating from granule cells, climbing fibers originating in the inferior olive, and inhibitory interneurons in the deep molecular layer (basket cells). However, the cellular distribution of CB1 in the cerebellar molecular layer has remained poorly understood. We used double fluorescence labelling to test for co-localization of nuclei with CB1 receptor protein. Labelling was intense surrounding nuclei in the deep and superficial molecular layer; consistent with basket cell and stellate cell inhibitory interneurons that regulate depolarization-induced suppression of inhibition (DSI) of Purkinje cells.

Animals↗

PubMed1976

Convergence on interneurones mediating the reciprocal Ia inhibition of motoneurones. I. Disynaptic Ia inhibition of Ia inhibitory interneurones.

Interneurones identified as mediating the disynaptic reciprocal Ia inhibition of motoneurones (referred to as "Ia inhibitory interneurones") were recorded in the lumbar spinal cord of the cat. It was revealed that the Ia inhibitory interneurones themselves receive disynaptic Ia inhibition. The muscles from which this inhibition is evoked are strictly antagonistic to those supplying their Ia excitation. Similar to the Ia inhibition in motoneurones the Ia inhibition in the Ia inhibitory interneurones is decreased when preceded by an antidromic stimulation of ventral roots. Furthermore, transmission of Ia inhibition to the Ia inhibitory interneurones is facilitated from ipsilateral and contralateral primary afferents as well as several supraspinal pathways analogous to earlier findings for the Ia inhibition of motoneurones. The pattern and control of the Ia inhibition of motoneurones and of Ia inhibitory interneurones display so striking similarities that it is suggested that identical interneurones are responsible. The conclusion thus emerges that "opposite" Ia inhibitory interneurones (i.e. interneurones monosynaptically connected to antagonistic muscles) are mutually inhibiting each other. The functional significance of this organization is discussed.

Afferent Pathways↗

PubMed1991

Simulations of cortical pyramidal neurons synchronized by inhibitory interneurons.

1. The interaction between inhibitory interneurons and cortical pyramidal neurons was studied by use of computer simulations to test whether inhibitory interneurons could assist in phase-locking postsynaptic cells. Two models were used: a simplified model, which included only 3 membrane channels, and a detailed 11-channel model. 2. The 11-channel model included most of the ion channels known to be present in neocortical pyramidal neurons as well as calcium diffusion and other membrane mechanisms. The kinetics for the channels were obtained from voltage-clamp studies in a variety of preparations. The parameters were then adjusted to produce repetitive bursting similar to that seen in some cortical pyramidal cells entrained during visual stimulation. 3. Phase-locking to a train of inhibitory postsynaptic potentials (IPSPs) located on or near the soma was observed in the 3-channel model cell subjected to random synaptic bombardment. In the 11-channel model, phase-locking due to multiple IPSPs was compared with phase-locking due to multiple excitatory postsynaptic potentials (EPSPs). Phase-locking began to occur when 20% of the IPSPs (20/100) or 40% of the EPSPs (4,000/10,000) were synchronized. The exact percentages differed with different 11-channel models, but either EPSPs or IPSPs would generally produce entrainment with approximately 40% synchronization. Thus 40 inhibitory boutons had an effect equivalent to 4,000 excitatory boutons in producing phase-locking. 4. Phase-locking with IPSPs in these models was possible because the IPSPs could cause either an increase or a decrease in firing rate over a limited range. The IPSPs served a modulatory role, increasing the rate of firing in some cases and decreasing it in others, depending on the state of the cell. 5. We examined frequency entrainment by IPSPs. In the 3-channel model, frequency entrainment of a postsynaptic cell was observed with a rapid train of strong (20-100 nS), brief, compound IPSPs. A 40-Hz compound IPSP train of 60 nS entrained cells having initial firing rates between 32 and 47 Hz. Below this range, cells could be partially entrained. Above the range, entrainment would fail. Frequency entrainment in the 3-channel model generally occurred on the first cycle after onset of the IPSPs. 6. Phase-locking and frequency entrainment were less robust in the 11-channel model. This was partly because bursts rather than individual spikes were being entrained. A 40-Hz, 90-nS compound IPSP train entrained a model cell upward from 34 Hz. Downward frequency entrainment also occurred.(ABSTRACT TRUNCATED AT 400 WORDS)

Calcium Channels↗

PubMed2003

Morphological development and neurochemical differentiation of cerebellar inhibitory interneurons in microexplant cultures.

The cerebellar cortex comprises a rather limited variety of interneurons, prominently among them inhibitory basket and stellate cells and Golgi neurons. To identify mechanisms subserving the positioning, morphogenesis, and neurochemical maturation of these inhibitory interneurons, we analyzed their development in primary microexplant cultures of the early postnatal cerebellar cortex. These provide a well-defined, patterned lattice within which the development of individual cells is readily accessible to experimental manipulation and observation. Pax-2-positive precursors of inhibitory interneurons were found to effectively segregate from granule cell perikarya. They emigrate from the core explant and avoid the vicinity of granule cells, which also emigrate and aggregate into small clusters around the explant proper. This contrasts with the behavior of Purkinje neurons, which remain within the explant proper. During migration, a subset of Pax-2-positive cells gradually acquires a GABAergic phenotype, and subsequently also expresses the type 2 metabotropic receptor for glutamate, or parvalbumin, markers for Golgi neurons and basket or stellate cells, respectively. The latter eventually orient their dendrites such that they take a preferentially perpendicular orientation relative to granule cell axons. Both the neurochemical maturation of basket/stellate cells and the specific orientation of their dendrites are independent of their continuous contact with radially oriented glia or Purkinje cell dendrites projecting from the core explant. Numbers of parvalbumin-positive basket/stellate cells and the prevalence of glutamate-positive neurites, which form a dense network preferentially within cell clusters containing granule cell perikarya and their dendrites, are subject to regulation by chronic depolarization. In contrast, brain-derived neurotrophic factor results in a drastic decrease of numbers of basket/stellate cells. These findings document that granule cell axons (parallel fibers) are the major determinant of basket/stellate cell dendritic orientation. They also show that the neurochemical maturation of cerebellar interneurons is sensitive to regulation by activity and neurotrophic factors.

Animals↗

PubMed2000

Membrane and synaptic actions of halothane on rat hippocampal pyramidal neurons and inhibitory interneurons.

A relatively small number of inhibitory interneurons can control the excitability and synchronization of large numbers of pyramidal neurons in hippocampus and other cortical regions. Thus, anesthetic modulation of interneurons could play an important role during anesthesia. The aim of this study was to investigate effects of a general anesthetic, halothane, on membrane and synaptic properties of rat hippocampal interneurons. GABA receptor-mediated IPSCs were recorded with whole-cell patch-clamp techniques in visually identified CA1 pyramidal cells and interneurons located at the border of stratum lacunosum-moleculare and stratum radiatum. Halothane (0.35 mm congruent with 1.2 vol%) depressed evoked IPSC amplitudes recorded from both pyramidal cells and inhibitory interneurons. Also, halothane considerably prolonged the decay time constant of evoked IPSCs in pyramidal cells and interneurons. The frequencies of miniature IPSCs were increased by halothane (two- to threefold) in both types of neuron. On the other hand, halothane effects on resting membrane potentials were variable but minimal in both types of neurons. In current-clamp recordings, halothane depressed EPSP amplitudes and increased IPSP amplitudes recorded from both types of neurons. In addition, halothane increased the failure rate of synaptically evoked action potentials. Taken together, these data provide evidence that halothane increases GABA(A) receptor-mediated synaptic inhibition between synaptically connected interneurons and depresses excitatory transmission, similar to effects observed in pyramidal neurons.

Action Potentials↗

PubMed2005

Relative contribution of Ia inhibitory interneurones to inhibition of feline contralateral motoneurones evoked via commissural interneurones.

The aim of the study was to examine to what extent the crossed inhibition of hindlimb lumbar alpha-motoneurones is evoked via interneurones that mediate reciprocal inhibition between flexors and extensors (Ia inhibitory interneurones), and to what extent via other spinal interneurones. The crossed inhibition was evoked by reticulospinal and vestibulospinal tract fibres, stimulated in the contralateral medullary longitudinal fascicle and the lateral vestibular nucleus, respectively, or by group II muscle afferents in the contralateral quadriceps nerve. The components of the IPSPs recorded in motoneurones that were mediated by Ia inhibitory interneurones were identified by their depression following activation of Renshaw cells. Trisynaptic components of IPSPs of reticulospinal and vestibulospinal origin, and polysynaptic (but not trisynaptic) components of IPSPs from group II afferents were found to be depressed in the majority of the motoneurones, while disynaptic components, those due to direct actions of inhibitory commissural interneurones, were not depressed. These results indicate that the coordination of left and right hindlimb movements based on crossed inhibition from reticulospinal and vestibulospinal neurones, depends on the degree of activation of Ia inhibitory interneurones by muscle spindle afferents and on their inhibition by Renshaw cells. Our results also indicate that Ia inhibitory interneurones do not operate as last-order inhibitory interneurones in crossed trisynaptic pathways from group II afferents, even though they mediate inhibition evoked by interneurones in shared polysynaptic pathways of crossed flexor and extensor reflexes coactivated by group II and other high-threshold muscle, skin and joint afferents.

Animals↗

PubMed1975

Recurrent inhibition of individual Ia inhibitory interneurones and disinhibition of their target alpha-motoneurones during muscle stretches.

The effects of ramp stretches applied to triceps surae muscle on the discharge patterns of single Ia inhibitory interneurones, monosynaptically invaded from various nerves, were studied in either decerebrate or anesthetized cats. Interneurones which received direct excitatory Ia input from the stretched muscle exhibited augmented activity both during the dynamic and static phase of stretch, which was, however, interrupted by a transient inhibitory influence during the dynamic phase of stretch. The influences on Ia inhibitory interneurones, monosynaptically invaded from hamstring or tibial nerve, were exclusively inhibitory. These stretch-induced inhibitions were better demonstrable in decerebrate than in anesthetized preparations. The timing of the discharge patterns of additionally recorded Renshaw cells during stretch, and the disappearance or reduction of the above described inhibitory effects after administration of DHE, strongly support the idea that these inhibitory actions are caused by Renshaw inhibition. In Ia inhibitory interneurones, monosynaptically activated from the antagonistic peroneal nerve, stretch induced also pronounced inhibitory effects, which were most probably caused by mutual inhibition between Ia inhibitory interneurones. The suppression of agonistic Ia inhibitory interneurone activity below the tonic resting activity corresponded to an enhancement of the monosynaptic reflex amplitude of the antagonistic motoneurone pool. The findings suggest that normal orthodromic activation of Renshaw cells, and consequently the recurrent inhibition of the Ia inhibitory interneurones, is predominantly linked with rapid phasic, rather than slow tonic, motoneuronal firing. The functional role of this mechanism for the performance of rapidly alternating movements and the damping of ballistic agonist contractions is discussed.

Animals↗

PubMed1985

Reciprocal inhibitory interneurones in the Xenopus embryo spinal cord.

The mechanism of reciprocal inhibition between antagonistic motor centres during swimming in the paralysed Xenopus embryo has been investigated further. Paired intracellular recordings have been made from interneurones and motoneurones in an attempt to identify neurones which make direct inhibitory synapses onto motoneurones on the opposite side of the spinal cord. A physiological class of inhibitory interneurones is described which, when stimulated by intracellular current passage, evoke short-latency, probably monosynaptic, strychnine-sensitive inhibitory potentials in contralateral motoneurones. These inhibitory interneurones fire once per swimming cycle in phase with the ipsilateral motor root discharge. They therefore have a pattern of activity which would cause them to inhibit motoneurones of the antagonistic motor centre at an appropriate part of the swimming cycle. The intracellular injection of horseradish peroxidase (HRP) has allowed the morphology of these inhibitory interneurones to be characterized. They have unipolar cell bodies with a thick proximal process with short dendrites which crosses the spinal cord ventrally and then bifurcates with one axonal branch ascending into the hind brain and the other descending the spinal cord. These anatomical features are typical of the 'commissural interneurones' first described by Roberts & Clarke (1982). There are also some inhibitory interneurones which can inhibit motoneurones on the same side of the spinal cord. At least some of these interneurones may be commissural interneurones with ipsilateral axons and they may play a role in the generation of the swimming rhythm.

Animals↗

PubMed2003

Comparison of the morphological and electrotonic properties of Renshaw cells, Ia inhibitory interneurons, and motoneurons in the cat.

The morphological and electrotonic properties of 4 motoneurons, 8 Ia inhibitory interneurons, and 4 Renshaw cells were compared. The morphological analysis, based on 3-D reconstructions of the cells, revealed that dendrites of motoneurons are longer and more extensively branched. Renshaw cells have dendrites that are shorter and simpler in structure. Dendrites of Ia inhibitory interneurons could be as long as those of motoneurons but the branching structure resembled that of Renshaw cells. Compartmental models were used to determine the electrotonic properties of the paths from each dendritic terminal to the soma. The attenuations of steady-state voltage changes in motoneurons were 3 and 7 times larger than in Ia inhibitory interneurons and Renshaw cells, respectively. The same relative order was observed for current attenuation and electrotonic length. The dendritic input resistances in Renshaw cells were 2 and 4 times larger than in Ia inhibitory interneurons and motoneurons, respectively. The difference in these electrotonic properties increased during higher synaptic activity as modeled by a decrease of Rm. The peak amplitudes of voltage transients at sites of brief, synaptic-like changes in conductance were highly dependent on cell class and were largest in Renshaw cells and smallest in motoneurons. In combination with class-specific differences in the attenuation of transient voltage signals, this led to large differences in the peak amplitudes of somatic voltage transients. Differences in the rise times and half-widths of the voltage transients were observed as well. Thus, based on passive properties, each cell class has a unique set of input/output properties.

Animals↗

PubMed2000

Temporal changes in the excitability of the reciprocal inhibitory interneurones preceding cocontraction of the antagonistic muscle in the human wrist.

The supraspinal control of reciprocal inhibitory interneurones preceding cocontraction of antagonistic muscles in the human wrist was investigated in 5 subjects. The method combined a reaction time task paradigm and a technique for conditioning the H-reflex. Unconditioned H-reflexes were elicited from flexor carpi radialis (FCR) and extensor carpi radialis (ECR) muscles by using electrical stimulation to median and radial nerves. The conditioned H-reflex of the FCR muscle was obtained by simultaneous electrical stimulation to the median and the radial nerves. While subjects performed the bilateral isometric cocontraction task, excitabilities of the alpha motoneurone pools and that of the reciprocal inhibitory interneurones were assessed by the unconditioned and conditioned H-reflex, respectively. Alpha mononeuron pools of FCR and ECR muscles were facilitated starting from approximately 50 msec. preceeding EMG activities. Reciprocal inhibitory interneurones which suppressed FCR alpha motoneurones were disinhibited at almost same time. The present results suggested that supraspinal control of the reciprocal inhibitory interneurones preceding antagonist cocontraction is different from that of preceding agonist contraction.

Adult↗

PubMed2002

Developmental expression of potassium-channel subunit Kv3.2 within subpopulations of mouse hippocampal inhibitory interneurons.

The developmental expression of the voltage-gated potassium channel subunit, Kv3.2, and its localization within specific mouse hippocampal inhibitory interneuron populations were determined using immunoblotting and immunohistochemical techniques. Using immunoblotting techniques, the Kv3.2 protein was weakly detected at postnatal age day 7 (P7), and full expression was attained at P21 in tissue extracts from homogenized hippocampal preparations. A similar developmental profile was observed using immunohistochemical techniques in hippocampal tissue sections. Kv3.2 protein expression was clustered on the somata and proximal dendrites of presumed inhibitory interneurons. Using double immunofluorescence, Kv3.2 subunit expression was detected on subpopulations of GABAergic inhibitory interneurons. Kv3.2 was detected in approximately 100% of parvalbumin-positive interneurons, 86% of interneurons expressing nitric oxide synthase, and approximately 50% of somatostatin-immunoreactive cells. Kv3.2 expression was absent from both calbindin- and calretinin-containing interneurons. Using immunoprecipitation, we further demonstrate that Kv3.2 and its related subunit Kv3.1b are coexpressed within the same protein complexes in the hippocampus. These data demonstrate that potassium channel subunit Kv3.2 expression is developmentally regulated in a specific set of interneurons. The vast majority of these interneuron subpopulations possess a "fast-spiking" phenotype, consistent with a role for currents through Kv3.2 containing channels in determining action potential kinetics in these cells.

Animals↗

PubMed2000

Characterization of neuronal migration disorders in neocortical structures: loss or preservation of inhibitory interneurons?

PURPOSE: Neuronal migration disorders (NMD) are often associated with therapy-resistant epilepsy. In human cerebral cortex, this hyperexcitability has been correlated with a loss of inhibitory interneurons. We used a rat model of focal cortical NMD (microgyria) to determine whether the expression of epileptiform activity in this model coincides with a decrease in inhibitory interneurons. METHODS: In 2-to 4-month-old rats, the density of interneurons immunoreactive for gamma-aminobutyric acid (GABA), calbindin, and parvalbumin was determined in fronto-parietal cortex in nine 200-microm-wide sectors located up to 2.5 mm lateral and 2.0 mm medial from the lesion center in primary parietal cortex (Par1). Quantitative measurements in homotopic areas of age-matched sham-operated rats served as controls. RESULTS: The freeze lesion performed in newborn rat cortex resulted in adult rats with a microgyrus extending in a rostro-caudal direction from frontal to occipital cortex. The density of GABA-and parvalbumin-positive neurons in fronto-parietal cortex was not significantly different between lesioned and control animals. Only the density of calbindin-immunoreactive neurons located 1.0 mm lateral and 0.5 mm medial from the lesion was significantly (Student t test, p < 0.05) larger in freeze-lesioned rats (5,817 +/- 562 and 6,400 +/- 795 cells per mm3, respectively; n = 12) compared with measurements in homotopic regions in Par1 cortex of controls (4,507 +/- 281 and 4, 061 +/- 319 cells per mm3, respectively; n = 5). CONCLUSIONS: The previously reported widespread functional changes in this model of cortical NMD are not related to a general loss of inhibitory interneurons. Other factors, such as a decrease in GABA receptor density, modifications in GABAA receptor subunit composition, or alterations in the excitatory network, e.g., an increase in the density of calbindin-immunoreactive pyramidal cells, more likely contribute to the global disinhibition and widespread expression of pathophysiological activity in this model of cortical NMD.

Adult↗

PubMed2001

Focal inhibitory interneuron loss and principal cell hyperexcitability in the rat hippocampus after microinjection of a neurotoxic conjugate of saporin and a peptidase-resistant analog of Substance P.

Episodes of prolonged seizures or head trauma produce chronic hippocampal network hyperexcitability hypothesized to result primarily from inhibitory interneuron loss or dysfunction. The possibly causal role of inhibitory neuron failure in the development of epileptiform pathophysiology remains unclear because global neurologic injuries produce such a multitude of effects. The recent finding that Substance P receptors (SPRs) are expressed exclusively in the rat hippocampus by inhibitory interneurons provided the rationale for attempting to ablate interneurons selectively by using neurotoxic conjugates of SPR ligands and the ribosome inactivating protein saporin that specifically target Substance P receptor-expressing cells. Whereas intrahippocampal microinjection of a conjugate of native SP and saporin produced significant nonspecific damage at concentrations needed to produce even limited selective loss of SPR-positive cells, a conjugate of saporin and the more potent and peptidase-resistant SP analog [Sar(9), Met(O(2))(11)] Substance P (SSP-saporin) caused negligible nonspecific damage at the injection site, and a virtually complete loss of SPR-like immunoreactivity (LI) up to 1 mm from the injection site. Within the SPR depletion zone, immunoreactivities for most GABA-, parvalbumin-, somatostatin-, and cholecystokinin-immunoreactive cells and fibers were eliminated. The few interneurons detectable within the affected zone were devoid of SPR-LI. The apparent loss of interneurons was selective in that calbindin- and glutamate receptor subunit 2 (GluR2) -positive principal cells survived within the affected zone, as did myelinated fibers and the extrinsic calretinin- and tyrosine hydroxylase--immunoreactive terminals of subcortical afferents. An apparent lack of reactive synaptic reorganization in response to interneuron loss was indicated by zinc transporter-3 (ZnT3)-- and beta-synuclein--LI, as well as by Timm staining, all of which revealed relatively normal patterns of excitatory terminal distribution. Control injections produced minor damage at the injection site, but no apparent specific loss of SPR-LI. One to 12 weeks after injection of SSP-saporin, extracellular electrophysiological field responses recorded in the CA1 pyramidal and dentate granule cell layers in response to afferent stimulation were blindly evaluated simultaneously in two sites 1-2 mm apart along the longitudinal hippocampal axis. SSP-saporin-treated rats exhibited relatively normal responses in some sites, whereas disinhibition and hyperexcitability indistinguishable from the pathophysiology produced by experimental status epilepticus were simultaneously recorded at adjacent sites. Anatomic analysis of the recording sites in each animal revealed that epileptiform pathophysiology was consistently observed only within areas of SPR ablation, whereas relatively normal evoked responses were recorded from immediately adjacent and relatively unaffected regions. These data establish the efficacy of [Sar(9), Met(O(2))(11)] Substance P-saporin for producing a selective and spatially extensive ablation of hippocampal inhibitory interneurons in vivo and a highly focal disinhibition that was restricted to the site of interneuron loss. These results also demonstrate that the "epileptic" pathophysiology produced by experimental status epilepticus or head trauma can be replicated by focal interneuron loss per se, without involving principal cell loss and other interpretive confounds inherent in the use of global neurologic injury models.

Animals↗