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PubMed2006

Generation of GABAergic and dopaminergic interneurons from endogenous embryonic olfactory bulb precursor cells.

During the embryonic period, many olfactory bulb (OB) interneurons arise in the lateral ganglionic eminence (LGE) from precursor cells expressing Dlx2, Gsh2 and Er81 transcription factors. Whether GABAergic and dopaminergic interneurons are also generated within the embryonic OB has not been studied thoroughly. In contrast to abundant Dlx2 and Gsh2 expression in ganglionic eminences (GE), Dlx2 and Gsh2 proteins are not expressed in the E12.5-13.5 mouse OB, whereas the telencephalic pallial domain marker Pax6 is abundant. We found GABAergic and dopaminergic neurons originating from dividing precursor cells in E13.5 OB and in short-term dissociated cultures prepared from the rostral half of E13.5 OB. In OB cultures, 22% of neurons were GAD+, of which 53% were Dlx2+, whereas none expressed Gsh2. By contrast, 70% of GAD+ cells in GE cultures were Dlx2+ and 16% expressed Gsh2. In E13.5 OB slices transplanted with EGFP-labeled E13.5 OB precursor cells, 31.7% of EGFP+ cells differentiated to GABAergic neurons. OB and LGE precursors transplanted into early postnatal OB migrated and differentiated in distinct patterns. Transplanted OB precursors gave rise to interneurons with dendritic spines in close proximity to synaptophysin-positive boutons. Interneurons were also abundant in differentiating OB neural stem cell cultures; the neurons responded to the neurotrophin Bdnf and expressed presynaptic proteins. In vivo, the Bdnf receptor TrkB colocalized with synaptic proteins at the glomeruli. These findings suggest that, in addition to receiving interneurons from the LGE, the embryonic OB contains molecularly distinct local precursor cells that generate mature GABAergic and dopaminergic neurons.

Animals↗
PubMed1978

Neuronal control of swimming in the medicinal leech. IV. Identification of a network of oscillatory interneurones.

Four oscillatory interneurones that appear to be the principal components of the central swim oscillator of Hirudo medicinalis have been identified on each side of the segmental ganglia of the ventral nerve cord. During 'swimming' episodes of an isolated nerve cord preparation each interneurone undergoes a polarization rhythm that is phase-locked with the impulse burst rhythm of the motor neurones known to drive the swimming movement. Passage of current into any of the interneurones can shift the phase of the swim rhythm. One of the interneurones projects its axon rearward to posterior ganglia and the other three project their axons frontward to anterior ganglia. The oscillatory interneurones are connected both intra- and interganglionically to form a topologically complex intersegmental network of concatenated ring circuits that possess the feature of recurrent cyclic inhibition. Theoretical analysis and electronic analogue models show that the network is inherently oscillatory and can produce both a cycle period and intra- and intersegmental phase relations of its elements that are appropriate for generating the body wave of the swimming movement.

Animals↗
PubMed1978

Neuronal control of swimming in the medicinal leech. V. Connexions between the oscillatory interneurones and the motor neurones.

A network of intra- and intersegmental synaptic connexions has been identified in the ventral nerve cord of the leech that links the set of oscillatory interneurones of the central swim oscillator to the motor neurones commanding the swimming rhythm. Excitatory connexions lead from oscillatory interneurones to both excitatory and inhibitory motor neurones, whereas inhibitory connexions lead from oscillatory interneurones to only the inhibitory motor neurones. Connexions leading from a motor neurone back to the oscillatory interneurones were found in only one exceptional case, an inhibitory motor neurone previously known to have access to the central swim oscillator. This network of identified connexions can account reasonably well for the mechanism by which the oscillatory interneurones drive their follower motor neurones into the phasic activity pattern characteristic of the swimming movement.

Action Potentials↗
PubMed2005

Conditional rhythmicity of ventral spinal interneurons defined by expression of the Hb9 homeodomain protein.

The properties of mammalian spinal interneurons that underlie rhythmic locomotor networks remain poorly described. Using postnatal transgenic mice in which expression of green fluorescent protein is driven by the promoter for the homeodomain transcription factor Hb9, as well as Hb9-lacZ knock-in mice, we describe a novel population of glutamatergic interneurons located adjacent to the ventral commissure from cervical to midlumbar spinal cord levels. Hb9+ interneurons exhibit strong postinhibitory rebound and demonstrate pronounced membrane potential oscillations in response to chemical stimuli that induce locomotor activity. These data provide a molecular and physiological delineation of a small population of ventral spinal interneurons that exhibit homogeneous electrophysiological features, the properties of which suggest that they are candidate locomotor rhythm-generating interneurons.

Animals↗
PubMed2005

Neural cell adhesion molecule-secreting transgenic mice display abnormalities in GABAergic interneurons and alterations in behavior.

The extracellular region of the transmembrane neural cell adhesion molecule (NCAM-EC) is shed as a soluble fragment at elevated levels in the schizophrenic brain. A novel transgenic mouse line was generated to identify consequences on cortical development and function of expressing soluble NCAM-EC from the neuron-specific enolase promoter in the developing and mature neocortex and hippocampus. NCAM-EC transgenic mice exhibited a striking reduction in synaptic puncta of GABAergic interneurons in the cingulate, frontal association cortex, and amygdala but not hippocampus, as shown by decreased immunolabeling of glutamic acid decarboxylase-65 (GAD65), GAD67, and GABA transporter 1. Interneuron cell density was unaltered in the transgenic mice. Affected subpopulations of interneurons included basket interneurons evident in NCAM-EC transgenic mice intercrossed with a reporter line expressing green fluorescent protein and by parvalbumin staining. In addition, there appeared to be a reduction in excitatory synapses, as revealed by synaptophysin staining and apical dendritic spine density of cortical pyramidal cells. Behavioral analyses demonstrated higher basal locomotor activity of NCAM-EC mice and enhanced responses to amphetamine and (+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine maleate compared with wild-type controls. Transgenic mice were deficient in prepulse inhibition, which was restored by clozapine but not by haloperidol. Additionally, NCAM-EC mice were impaired in contextual and cued fear conditioning. These results suggested that elevated shedding of NCAM perturbs synaptic connectivity of GABAergic interneurons and produces abnormal behaviors that may be relevant to schizophrenia and other neuropsychiatric disorders.

Amphetamine↗
PubMed2006

Glutamate acting on AMPA but not NMDA receptors modulates the migration of hippocampal interneurons.

Paracrine GABA and glutamate acting, respectively, on GABAA and NMDA receptors modulate the migration of hippocampal pyramidal cells. Using corticohippocampal organotypic explants from glutamic acid decarboxylase (GAD) 67-enhanced green fluorescent protein (EGFP) knock-in embryos, we now report that, in contrast to pyramidal neurons, the blockade of AMPA but not NMDA receptors exerts important actions on the migration of GABAergic interneurons. In addition, the blockade of GABAA receptors fails to modify the migration rates of GABAergic interneurons. Immunohistochemical analyses of GAD67-EGFP embryos (from embryonic day 14 to birth) reveal that interneurons colonize the hippocampal primordium by embryonic day 15. At that stage, the hippocampal primordium is already composed of pioneer glutamatergic neurons, including (1) Cajal-Retzius cells, immunopositive to calretinin and reelin, and (2) other presumptive pioneer pyramidal cells that are immunopositive to betaIII-tubulin and vesicular glutamate transporter 3 and immunonegative to GABA or GAD67. Therefore, the migrations of pyramidal neurons and GABAergic interneurons are cross-modulated: glutamate released from pioneer glutamatergic neurons facilitates the migration of GABAergic interneurons, which in turn would release GABA, facilitating the migration of glutamatergic neuroblasts. This general sequence may provide a retroactive positive loop needed to construct the hippocampal network. It might constitute a primitive homeostatic mechanism in the developing brain that acts to balance GABA-glutamate contributions to network construction and activity.

6-Cyano-7-nitroquinoxaline-2,3-dione↗
PubMed2006

TASK-like conductances are present within hippocampal CA1 stratum oriens interneuron subpopulations.

TASK-1 (KCNK3) and TASK-3 (KCNK9) are members of the two-pore domain potassium channel family and form either homomeric or heteromeric open-rectifier (leak) channels. Recent evidence suggests that these channels contribute to the resting potential and input resistance in several neuron types, including hippocampal CA1 pyramidal cells. However, the evidence for TWIK-related acid-sensitive potassium (TASK)-like conductances in inhibitory interneurons is less clear, and mRNA expression has suggested that TASK channels are expressed in only a subpopulation of interneurons. Here we use immunocytochemistry to demonstrate prominent TASK-3 protein expression in both parvalbumin-positive- and a subpopulation of glutamic acid decarboxylase (GAD)67-positive interneurons. In addition, a TASK-like current (modulated by both pH and bupivacaine) was detected in 30-50% of CA1 stratum oriens interneurons of various morphological classes. In most neurons, basic shifts in pH had a larger effect on the TASK-like current than acidic, suggesting that the current is mediated by TASK-1/TASK-3 heterodimers. These data suggest that TASK-like conductances are more prevalent in inhibitory interneurons than previously supposed.

Animals↗
PubMed2006

GABAergic input onto CA3 hippocampal interneurons remains shunting throughout development.

In hippocampus, the net flow of excitability is controlled by inhibitory input provided by the many populations of local circuit inhibitory interneurons. In principal cells, GABA(A) receptor-mediated synaptic input undergoes a highly coordinated shift from depolarizing early in life to a more conventional hyperpolarizing inhibition on maturation. This switch in inhibitory input polarity is controlled by the developmental regulation of two chloride cotransporters (NKCC1 and KCC2) that results in a net shift from high to low intracellular Cl(-). Whether inhibitory input onto inhibitory interneurons demonstrates a similar developmental shift in intracellular Cl(-) is unexplored. Using the gramicidin perforated-patch configuration, we recorded from CA3 hippocampal stratum lucidum interneurons and pyramidal cells to monitor inhibitory input across a broad developmental range. GABA(A) receptor-mediated synaptic input onto stratum lucidum inhibitory interneurons was shunting in nature across the entire developmental age range tested, as resting membrane potential and the IPSC reversal potential remained within a few millivolts (1-4 mV) between postnatal day 5 (P5) and P31. Furthermore, sensitivity to block of the two chloride cotransporters KCC2 and NKCC1 did not differ across the same age range, suggesting that their relative expression is fixed across development. In contrast, pyramidal cell synaptic inhibition demonstrated the well described switch from depolarizing to hyperpolarizing over the same age range. Thus, in contrast to principal cells, inhibitory synaptic input onto CA3 interneurons remains shunting throughout development.

Age Factors↗
PubMed2006

Somatodendritic Kv7/KCNQ/M channels control interspike interval in hippocampal interneurons.

The M-current (I(M)), comprised of Kv7 channels, is a voltage-activated K+ conductance that plays a key role in the control of cell excitability. In hippocampal principal cells, I(M) controls action potential (AP) accommodation and contributes to the medium-duration afterhyperpolarization, but the role of I(M) in control of interneuron excitability remains unclear. Here, we investigated I(M) in hippocampal stratum oriens (SO) interneurons, both from wild-type and transgenic mice in which green fluorescent protein (GFP) was expressed in somatostatin-containing interneurons. Somatodendritic expression of Kv7.2 or Kv7.3 subunits was colocalized in a subset of GFP+ SO interneurons, corresponding to oriens-lacunosum moleculare (O-LM) cells. Under voltage clamp (VC) conditions at -30 mV, the Kv7 channel antagonists linopirdine/XE-991 abolished the I(M) amplitude present during relaxation from -30 to -50 mV and reduced the holding current (I(hold)). In addition, 0.5 mM tetraethylammonium reduced I(M), suggesting that I(M) was composed of Kv7.2-containing channels. In contrast, the Kv7 channel opener retigabine increased I(M) amplitude and I(hold). When strongly depolarized in VC, the linopirdine-sensitive outward current activated rapidly and comprised up to 20% of the total current. In current-clamp recordings from GFP+ SO cells, linopirdine induced depolarization and increased AP frequency, whereas retigabine induced hyperpolarization and arrested firing. In multicompartment O-LM interneuron models that incorporated I(M), somatodendritic placement of Kv7 channels best reproduced experimentally measured I(M). The models suggest that Kv3- and Kv7-mediated channels both rapidly activate during single APs; however, Kv3 channels control rapid repolarization of the AP, whereas Kv7 channels primarily control the interspike interval.

Action Potentials↗
PubMed2005

Differential regulation of metabotropic glutamate receptor- and AMPA receptor-mediated dendritic Ca2+ signals by presynaptic and postsynaptic activity in hippocampal interneurons.

Calcium plays a crucial role as a ubiquitous second messenger and has a key influence in many forms of synaptic plasticity in neurons. The spatiotemporal properties of dendritic Ca2+ signals in hippocampal interneurons are relatively unexplored. Here we use two-photon calcium imaging and whole-cell recordings to study properties of dendritic Ca2+ signals mediated by different glutamate receptors and their regulation by synaptic activity in oriens/alveus (O/A) interneurons of rat hippocampus. We demonstrate that O/A interneurons express Ca2+-permeable AMPA receptors (CP-AMPARs) providing fast Ca2+ signals. O/A cells can also coexpress CP-AMPARs, Ca2+-impermeable AMPARs (CI-AMPARs), and group I/II metabotropic glutamate receptors (mGluRs) (including mGluR1a), in the same cell. CI-AMPARs are often associated with mGluRs, resulting in longer-lasting Ca2+ signals than CP-AMPAR-mediated responses. Finally, CP-AMPAR- and mGluR-mediated Ca2+ signals demonstrate distinct voltage dependence and are differentially regulated by presynaptic and postsynaptic activity: weak synaptic stimulation produces Ca2+ signals mediated by CP-AMPARs, whereas stronger stimulation, or weak stimulation coupled with postsynaptic depolarization, recruits Ca2+ signals mediated by mGluRs. Our results suggest that differential activation of specific glutamate receptor-mediated Ca2+ signals within spatially restricted dendritic microdomains may serve distinct signaling functions and endow oriens/alveus interneurons with multiple forms of Ca2+-mediated synaptic plasticity. Specific activation of mGluR-mediated Ca2+ signals by coincident presynaptic and postsynaptic activity fulfills the conditions for Hebbian pairing and likely underlies their important role in long-term potentiation induction at O/A interneuron synapses.

Animals↗
PubMed2002

The spatial dimensions of electrically coupled networks of interneurons in the neocortex.

Inhibitory interneurons of the neocortex are electrically coupled to cells of the same type through gap junctions. We studied the spatial organization of two types of interneurons in the rat somatosensory cortex: fast-spiking (FS) parvalbumin-immunoreactive (PV+) cells, and low threshold-spiking (LTS) somatostatin-immunoreactive (SS+) cells. Paired recordings in layer 4 demonstrated that both the probability of coupling and the coupling coefficient drop steeply with intersomatic distance, reaching zero beyond 200 microm. The dendritic arbors of FS and LTS cells were reconstructed from electrophysiologically characterized, biocytin-filled cells; the two cell types had only minor differences in the number and span of their dendrites. However, there was a markedly higher density of PV+ cells than SS+ cells. PV+ cells were densest in layer 4, while SS+ cell density peaked in the subgranular layers. From these data we estimate that there is measurable electrical coupling (directly or indirectly via intermediary cells) between each interneuron and 20-50 others. The large number of electrical synapses implies that each interneuron participates in a large, continuous syncytium. To evaluate the functional significance of these findings, we examined several simple architectures of coupled networks analytically. We present a mathematical method to estimate the average summated coupling conductance that each cell receives from all of its neighbors, and the average leak conductance of individual cells, and we suggest that these have the same order of magnitude. These quantitative results have important implications for the effects of electrical coupling on the dynamic behavior of interneuron networks.

Action Potentials↗
PubMed1999

Apparent loss and hypertrophy of interneurons in a mouse model of neuronal ceroid lipofuscinosis: evidence for partial response to insulin-like growth factor-1 treatment.

The neuronal ceroid lipofuscinoses (NCL) are progressive neurodegenerative disorders with onset from infancy to adulthood that are manifested by blindness, seizures, and dementia. In NCL, lysosomes accumulate autofluorescent proteolipid in the brain and other tissues. The mnd/mnd mutant mouse was first characterized as exhibiting adult-onset upper and lower motor neuron degeneration, but closer examination revealed early, widespread pathology similar to that seen in NCL. We used the autofluorescent properties of accumulated storage material to map which CNS neuronal populations in the mnd/mnd mouse show NCL-like pathological changes. Pronounced, early accumulation of autofluorescent lipopigment was found in subpopulations of GABAergic neurons, including interneurons in the cortex and hippocampus. Staining for phenotypic markers normally present in these neurons revealed progressive loss of staining in the cortex and hippocampus of mnd/mnd mice, with pronounced hypertrophy of remaining detectable interneurons. In contrast, even in aged mutant mice, many hippocampal interneurons retained staining for glutamic acid decarboxylase. Treatment with insulin-like growth factor-1 partially restored interneuronal number and reduced hypertrophy in some subregions. These results provide the first evidence for the involvement of interneurons in a mouse model of NCL. Moreover, our findings suggest that at least some populations of these neurons persist in a growth factor-responsive state.

Aging↗
PubMed1999

Choline and selective antagonists identify two subtypes of nicotinic acetylcholine receptors that modulate GABA release from CA1 interneurons in rat hippocampal slices.

Neuronal nicotinic receptors (nAChR) are known to control transmitter release in the CNS. Thus, this study was aimed at exploring the diversity and localization of nAChRs present in CA1 interneurons in rat hippocampal slices. The use of a U-tube as the agonist delivery system was critical for the reliable detection of nicotinic responses induced by brief exposure of the neurons to ACh or to the alpha7 nAChR-selective agonist choline. The present study demonstrated that CA1 interneurons, in addition to expressing functional alpha7 nAChRs, also express functional alpha4beta2-like nAChRs and that activation of both receptors facilitates an action potential-dependent release of GABA. Depending on the experimental condition, one of the following nicotinic responses was recorded from the interneurons by means of the patch-clamp technique: a nicotinic whole-cell current, depolarization accompanied by action potentials, or GABA-mediated postsynaptic currents (PSCs). Responses mediated by alpha7 nAChRs were short-lasting, whereas those mediated by alpha4beta2 nAChRs were long-lasting. Thus, phasic or tonic inhibition of CA1 interneurons may be achieved by selective activation of alpha7 or alpha4beta2 nAChRs, respectively. It can also be suggested that synaptic levels of choline generated by hydrolysis of ACh in vivo may be sufficient to control the activity of the alpha7 nAChRs. The finding that methyllycaconitine and dihydro-beta-erythroidine (antagonists of alpha7 and alpha4beta2 nAChRs, respectively) increased the frequency and amplitude of GABAergic PSCs suggests that there is an intrinsic cholinergic activity that sustains a basal level of nAChR activity in these interneurons.

Action Potentials↗
PubMedDate not supplied

Two modulatory inputs exert reciprocal reinforcing effects on synaptic input of premotor interneurons for withdrawal in terrestrial snails.

A cluster of serotonergic cells in the rostral part of pedal ganglia of the terrestrial snail Helix lucorum was shown previously to participate in modulation of withdrawal behavior, and to be necessary for elaboration of aversive withdrawal conditioning in intact snails. In the present experiments local extracellular stimulation of the serotonergic cells elicited a pairing-specific increase (difference between paired and explicitly unpaired sessions was significant, P<0.01) of synaptic responses in the premotor interneurons involved in withdrawal to paired nerve stimulation. Intracellular stimulation of only one Pd4 cell from the pedal group of serotonergic neurons increased (P<0.05) synaptic responses to contingent test nerve stimulation significantly in the same premotor interneurons for 2-3 hr. Mesocerebral cells are known to participate in male sexual behavior, and their extracellular stimulation was shown previously to suppress the amplitude of synaptic responses in withdrawal interneurons. Local extracellular stimulation of the mesocerebral cells elicited a pairing-specific decrease (P<0.01) of synaptic responses to contingent test nerve stimulation in the premotor interneurons involved in withdrawal for 2-3 hr. Paired application of met-enkephaline (10(-6) M, some mesocerebral cells are enkephaline-like immunoreactive) also selectively decreased synaptic responses to contingent nerve stimulation in the premotor interneurons for hours. Thus, two modulatory inputs exert pairing-specific effects that influence the same synaptic connection in opposite directions, which may underlie the long-term up- and down-regulation of behavioral responses.

Animals↗
PubMed1999

Action of ethanol on responses to nicotine from cerebellar interneurons and medial septal neurons: relationship to methyllycaconitine inhibition of nicotine responses.

BACKGROUND: A majority of alcoholics also smoke, suggesting that alcohol and nicotine share a common action on nicotinic cholinergic receptors. METHODS: Extracellular single-unit recording was used to investigate the effects of ethanol on responses to nicotine from rat cerebellar interneurons and medial septal neurons. RESULTS: Nicotine produced inhibition from medial septal neurons, but increased neural activity of cerebellar interneurons. When ethanol was applied locally to cerebellar interneurons, the excitatory response to nicotine was enhanced in a dose-related manner. Nicotine-induced inhibition from medial septal neurons was reduced by ethanol from the majority of neurons, but a dose relationship for this inhibition by ethanol was not observed. Ethanol affected responses to nicotine from over 90% of all neurons investigated at these sites. Initially, it was established that the nicotinic antagonists, methyllycaconitine (MLA) and alpha-bungarotoxin, which affect a nicotinic cholinergic (nACh) receptor with an alpha7 subunit, had similar actions on responses to nicotine from individual medial septal cells and cerebellar interneurons. When MLA was tested against responses to nicotine from neurons in the two brain regions, MLA antagonized responses to nicotine from only 27% of the neurons rather than the 90% found for ethanol. This latter observation provided evidence that ethanol was affecting neurons with MLA-insensitive receptors. When the actions of ethanol on responses to nicotine were compared directly with the action of MLA on the same medial septal neurons, both ethanol and MLA caused a greater than 50% antagonism of the response to nicotine, indicative that nACh receptors with the alpha7 subunit were sensitive to ethanol. CONCLUSIONS: Collectively, these data provide evidence that ethanol affects responses to nicotine not only from nACh receptors on medial septal cells and cerebellar interneurons containing an alpha7 subunit (i.e., MLA-sensitive receptors), but also from nACh receptor subtypes without this specific nACh receptor subunit (i.e., MLA-insensitive receptors).

Aconitine↗
PubMed2000

Differential innervation of parvalbumin-immunoreactive interneurons of the basolateral amygdaloid complex by cortical and intrinsic inputs.

In the basolateral (BL) amygdaloid complex, the excitability of projection cells is regulated by intrinsic inhibitory interneurons using gamma-aminobutyric acid (GABA) as a transmitter. A subset of these cells are labeled in a Golgi-like manner by Parvalbumin (PV) immunohistochemistry. Recently, we have shown that the overwhelming majority of axon terminals contacting these PV-immunoreactive neurons form asymmetric synapses. The present study was undertaken to identify the source(s) of these inputs. Since previous work had revealed that thalamic axons form very few synapses on BL interneurons (< 1%), we focused on cortical and intra-amygdaloid inputs. Iontophoretic injections of the anterograde tracers Phaseolus vulgaris-leucoagglutinin or biotinylated dextran amine were performed in various cortical fields in cats (perirhinal, entorhinal, pre/infralimbic cortices) and monkeys (orbitofrontal region) or in the BL amygdaloid nucleus in cats. These injections resulted in a large number of anterogradely labeled terminals forming asymmetric synapses in the BL complex. Following cortical injections, numerous anterogradely labeled terminals were found in the vicinity of PV-immunoreactive interneurons in the BL amygdala. However, only approximately 1% of these terminals formed synaptic contacts with PV-immunoreactive profiles. In contrast, as many as 11% of the terminals contributed by the intranuclear axon collaterals of BL projection cells established synapses with PV-immunoreactive elements. Since the axon terminals of PV-immunoreactive interneurons are enriched in GABA and they exclusively form symmetric synapses, these results suggest that PV-immunoreactive interneurons are predominantly involved in feedback inhibition in the BL amygdaloid complex.

Amygdala↗
PubMed2000

Deficit of striatal parvalbumin-reactive GABAergic interneurons and decreased basal ganglia output in a genetic rodent model of idiopathic paroxysmal dystonia.

The underlying mechanisms of various types of hereditary dystonia, a common movement disorder, are still unknown. Recent findings in a genetic model of a type of paroxysmal dystonia, the dt(sz) mutant hamster, pointed to striatal dysfunctions. In the present study, immunhistochemical experiments demonstrated a marked decrease in the number and density of parvalbumin-immunoreactive GABAergic interneurons in all striatal subregions of mutant hamsters. To examine the functional relevance of the reduction of these inhibitory interneurons, the effects of the GABA(A) receptor agonist muscimol on severity of dystonia were examined after microinjections into the striatum and after systemic administrations. Muscimol improved the dystonic syndrome after striatal injections to a similar extent as after systemic treatment, supporting the importance of the deficiency of striatal GABAergic interneurons for the occurrence of the motor disturbances. The disinhibition of striatal GABAergic projection neurons, as suggested by recent extracellular single-unit recordings in dt(sz) hamsters, should lead to an abnormal neuronal activity in the basal ganglia output nuclei. Indeed, a significantly decreased basal discharge rate of entopeduncular neurons was found in dt(sz) hamsters. We conclude that a deficit of striatal GABAergic interneurons leads by disinhibition of striatal GABAergic projection neurons to a reduced activity in the entopeduncular nucleus, i.e., to a decreased basal ganglia output. This finding is in line with the current hypothesis about the pathophysiology of hyperkinesias. The results indicate that striatal interneurons deserve attention in basic and clinical research of those movement disorders.

Action Potentials↗
PubMed2001

Stimulation of nitric oxide-cGMP pathway excites striatal cholinergic interneurons via protein kinase G activation.

Conflicting data have been collected so far on the action of nitric oxide (NO) on cholinergic interneurons of the striatum. In the present in vitro electrophysiological study, we reported that intracellularly recorded striatal cholinergic interneurons are excited by both hydroxylamine and S-nitroso-N-acetylpenicillamine, two NO donors. This excitation persisted unchanged in the presence of glutamate, dopamine, and substance P receptor antagonists as well as after blockade of tetrodotoxin (TTX)- and calcium channel-sensitive transmitter release, suggesting that NO produces its effects by modulating directly resting ion conductances in the somatodendritic region of striatal cholinergic cells. The depolarizing effect of hydroxylamine was greatly reduced by lowering external concentrations of sodium ions (from 126 to 38 mm) and did not reverse polarity in the voltage range from -120 to -40 mV. The sodium transporter blockers bepridil and 3',4'-dichlorobenzamil were conversely ineffective in preventing NO-induced membrane depolarization. Intracellular cGMP elevation is required for the action of hydroxylamine on striatal cholinergic cells, as demonstrated by the findings that the membrane depolarization produced by this pharmacological agent was prevented by bath and intracellular application of two inhibitors of soluble guanylyl cyclase and was mimicked and occluded by zaprinast, a cGMP phosphodiesterase inhibitor. Finally, intracellular Rp-8-Br-cGMPS, a protein kinase G (PKG) inhibitor, blocked the hydroxylamine-induced membrane depolarization of cholinergic interneurons, whereas both okadaic acid and calyculin A, two protein phosphatase inhibitors, enhanced it, indicating that intracellular PKG and phosphatases oppositely regulate the sensitivity of striatal cholinergic interneurons to NO. The characterization of the cellular mechanisms involved in the regulation of striatal interneuron activity is a key step for the understanding of the role of these cells in striatal microcircuitry.

3',5'-Cyclic-GMP Phosphodiesterases↗