Large Aspiny Neurons Research Articles

Editorial: Brain cholinergic mechanisms.

Editorial: Brain cholinergic mechanisms.

Up-Regulation of A-Type Potassium Currents Protects Neurons Against Cerebral Ischemia

Excitotoxicity is the major cause of many neurologic disorders including stroke. Potassium currents modulate neuronal excitability and therefore influence the pathological process. A-type potassium current (I(A)) is one of the major voltage-dependent potassium currents, yet its roles in excitotoxic cell death are not well understood. We report that, following ischemic insults, the I(A) increases significantly in large aspiny (LA) neurons but not medium spiny (MS) neurons in the striatum, which correlates with the higher resistance of LA neurons to ischemia. Activation of protein kinase Cα increases I(A) in LA neurons after ischemia. Cultured neurons from transgenic mice lacking both Kv1.4 and Kv4.2 subunits exhibit an increased vulnerability to ischemic insults. Increase of I(A) by recombinant expression of Kv1.4 or Kv4.2 is sufficient in improving the survival of MS neurons against ischemic insults both in vitro and in vivo. These results, taken together, provide compelling evidence for a protective role of I(A) against ischemia.

Increased GAD expression in the striatum after transient cerebral ischemia

Striatum is one of the brain regions that are highly sensitive to transient cerebral ischemia. Most of the striatal neurons die shortly after ischemia but interneurons including large aspiny (LA) neurons survive the same insult. Previous studies have shown that inhibitory synaptic transmission is enhanced in LA neurons after ischemia. The present study is aimed at revealing the mechanisms underlying this phenomenon. Immunohistochemical studies and Western blotting were performed to examine the expression of glutamic decarboxylase (GAD), the key enzyme in the synthesis of GABA, in the striatum. GAD65 expression and the number of GAD67-positive cells were increased after ischemia. GAD67-positive cells in the striatum co-expressed GAD65 after ischemia. The increase of GAD67-positive cells did not result from neurogenesis. Double-labeling of GAD67 and SOM indicates that some of the GAD67-positive cells are from the phenotypic shift of pre-existing somatostatin (SOM)-containing GABAergic interneurons after ischemia. Facilitation of inhibitory synaptic transmission by muscimol, a specific GABAA receptor agonist, increased the number of survived cells in the striatum after ischemia. Altogether, these data suggest that GAD expression is increased in the striatum after ischemia, which might contribute to the facilitated inhibitory synaptic transmission and the consequent survival of LA neurons.

Many Roads to Motor Deficits: Loss of Dopamine Signaling in Direct or Indirect Basal Ganglia Pathway Leads to Akinesia through Distinct Physiological Mechanisms

action of DA at both or either population of receptors using the specific D1 and D2 antagonists, SCH-23390 and raclopride, respectively. Electrode microarrays chronically implanted in the dorsal striata of freely moving mice monitored changes in single unit and local field potential (LFP) activity following administration of the antagonists. The authors discriminated between the primary output neurons of the dorsal striatum, the medium spiny neurons (MSNs), and the fast-spiking interneurons and large aspiny neurons based upon the half-width, firing frequency, and ampli tude of the recorded waveforms. Single unit firing rate, relative power of differ ent frequency oscillations in the LFP, and entrainment of firing to the LFP (meas ured as spike-triggered average) were con

Enhancement of inhibitory synaptic transmission in large aspiny neurons after transient cerebral ischemia

Large aspiny neurons and most of the GABAergic interneurons survive transient cerebral ischemia while medium spiny neurons degenerate in 24 h. Expression of a long-term enhancement of excitatory transmission in medium spiny neurons but not in large aspiny neurons has been indicated to contribute to this selective vulnerability. Because neuronal excitability is determined by the counterbalance of excitation and inhibition, the present study examined inhibitory synaptic transmission in large aspiny neurons after ischemia in rats. Transient cerebral ischemia was induced for 22 min using the four-vessel occlusion method and whole-cell voltage-clamp recording was performed on striatal slices. The amplitudes of evoked inhibitory postsynaptic currents in large aspiny neurons were significantly increased at 3 and 24 h after ischemia, which was mediated by the increase of presynaptic release. Postsynaptic responses were depressed at 24 h after ischemia. Inhibitory postsynaptic currents could be evoked in large aspiny neurons at 24 h after ischemia, suggesting that they receive GABAergic inputs from the survived GABAergic interneurons. Muscimol, a GABA A receptor agonist, presynaptically facilitated inhibitory synaptic transmission at 24 h after ischemia. Such facilitation was dependent on the extracellular calcium and voltage-gated sodium channels. The present study demonstrates an enhancement of inhibitory synaptic transmission in large aspiny neurons after ischemia, which might reduce excitotoxicity and contribute, at least in part, to the survival of large aspiny neurons. Our data also suggest that large aspiny neurons might receive inhibitory inputs from GABAergic interneurons.

Dopamine induced switch in the subthreshold dynamics of the striatal cholinergic interneurons: A numerical study

The striatum is a part of the basal ganglia, which are a group of nuclei in the brain associated with motor control, cognition and learning. Striatal cholinergic interneurons (AchNs) play a crucial role in these functions. AchNs are tonically active in vivo and in vitro, and are able to fire in the absence of synaptic inputs. AchNs respond to sensory stimuli and sensorimotor learning by transiently suppressing their firing activity. This pause is dopamine signal sensitive, but the neurophysiological mechanism of the dopaminergic influence is under debate. Both the regular spiking response as well as the pause response are influenced by the inwardly rectifying outward G kir , a slow hyperpolarization activated noninactivating G h , and calcium and calcium-dependent potassium conductances [Wilson, C., Goldberg, J., 2006. Origin of the slow afterhyperpolarization and slow rhythmic bursting in striatal cholinergic interneurons. J. Neurophysiol. 95(1), 196–204; Wilson, C., 2005. The mechanism of intrinsic amplification of hyperpolarizations and spontaneous bursting in striatal cholinergic interneurons. Neuron 45(4), 575–585]. Recent experimental evidence has shown that dopaminergic modulations on G h , G kir and calcium conductances influence the AchN's excitability [Deng, P., Zhang, Y., Xu, Z., 2007. Involvement of I( h) in dopamine modulation of tonic firing in striatal cholinergic interneurons. J. Neurosci. 27(12), 3148–3156; Aosaki, T., Kiuchi, K., Kawaguchi, Y., 1998. Dopamine D 1 -like receptor activation excites rat striatal large aspiny neurons in vitro. J. Neurosci. 18(14), 5180–5190]. We employed computational models of the AchN to analyze the conductance based dopaminergic changes. We analyzed the robustness of these subthreshold oscillations and how they are affected by dopaminergic modulation. Our results predict that these conductances allow the dopamine to switch the AchN between stable oscillatory and fixed-point behaviors. The present approach and results show that dopamine receptors ( D 1 and D 2 ) mediate opposing effects on this switch and therefore on the suprathreshold excitability as well. The switching effect of the dopaminergic signal is the major qualitative feature that can serve as a building block for higher network-level descriptions. To our knowledge this is the first paper that synthesizes the growing body of experimental literature about the dopaminergic modulation of the AchNs into a modelling framework.

Increase of delayed rectifier potassium currents in large aspiny neurons in the neostriatum following transient forebrain ischemia

Large aspiny (LA) neurons in the neostriatum are resistant to cerebral ischemia whereas spiny neurons are highly vulnerable to the same insult. Excitotoxicity has been implicated as the major cause of neuronal damage after ischemia. Voltage-dependent potassium currents play important roles in controlling neuronal excitability and therefore influence the ischemic outcome. To reveal the ionic mechanisms underlying the ischemia-resistance, the delayed rectifier potassium currents ( I k) in LA neurons were studied before and at different intervals after transient forebrain ischemia using brain slices and acute dissociation preparations. The current density of I k increased significantly 24 h after ischemia and returned to control levels 72 h following reperfusion. Among currents contributing to I k, the margatoxin-sensitive currents increased 24 h after ischemia while the KCNQ/M current remained unchanged after ischemia. Activation of protein kinase A (PKA) down-regulated I k in both control and ischemic LA neurons, whereas inhibition of PKA only up-regulated I k and margatoxin-sensitive currents 72 h after ischemia, indicating an active PKA regulation on I k at this time. Protein tyrosine kinases had a tonic inhibition on I k to a similar extent before and after ischemia. Compared with that of control neurons, the spike width was significantly shortened 24 h after ischemia due to facilitated repolarization, which could be reversed by blocking margatoxin-sensitive currents. The increase of I k in LA neurons might be one of the protective mechanisms against ischemic insult.

Histopathologic and Morphometric Studies on the Rat Brain after Repeated Administration of Cocaine

The brain of cocaine administrated rats was histopathologically investigated by light and electron microscopy. The examined regions were the nucleus accumbens core and shell, and the striatum pars dorsolateral. Morphometric analyses concerning the density of dendritic spines and the number of large aspiny neurons were also performed. A total of 15 male rats, 8-week-old, were used as experimental animals. Cocaine HCL was intraperitoneally injected into the rat at a dose of 15 mg/kg/day for 2 weeks. These rats were divided into three groups based on examination purposes such as staining techniques for histology and electron microscopy. As a control group, a total of 15 rats were injected with 0.9% saline solution. In the cocaine administrated rats, the density of dendritic spines on medium spiny neurons in the above three regions were increased compared with that of the control group. At the ultrastructure level, the dendritic spines were frequently observed in the experimental group. The large aspiny neurons of the striatum pars dorsolateral in the experimental group showed a tendency to increase in number. These findings were statistically supported by morphometric analyses. From these obtained results, it is suggested that the increase of dendritic spines and of large aspiny neurons might be induced by cocaine administration, and these facts might cause the alteration of synaptic connectivity pattern in mesocorticolimbic dopmine circuitry.

Developmental changes of transient potassium currents in large aspiny neurons in the neostriatum

Developmental regulation of the potassium conductance is important for the maturation of neuronal excitability and the formation of functional circuitry in the central nervous system (CNS). The rapidly inactivating A-type current is a major component of the voltage-dependent outward potassium currents in the large aspiny (LA) neurons in the neostriatum. The large aspiny neurons play important roles in the function of neostriatum in physiological and pathological conditions. Whole-cell patch-clamp recording was performed on acutely dissociated neurons and brain slices to investigate the postnatal development of A-type current in the large aspiny neurons. The current density of A-type current in large aspiny neurons was the highest at postnatal 1–3 days and gradually decreased during the development with the lowest levels in adult animals. In comparison to postnatal 1–3 days, the steady-state inactivation curve shifted in depolarizing direction in mature neurons. No significant changes in the voltage dependence of steady-state activation were observed during development. Consistent with the decrease in the current density of A-type current during development, the latency to the first spike was dramatically shortened in mature large aspiny neurons. These results suggest that the decrease of rapidly inactivating A-type potassium current during development might contribute, at least in part, to the maturation of the membrane excitability of large aspiny neurons in the neostriatum.

Depression of Fast Excitatory Synaptic Transmission in Large Aspiny Neurons of the Neostriatum after Transient Forebrain Ischemia

Spiny neurons in the neostriatum die within 24 hr after transient global ischemia, whereas large aspiny (LA) neurons remain intact. To reveal the mechanisms of such selective cell death after ischemia, excitatory neurotransmission was studied in LA neurons before and after ischemia. The intrastriatally evoked fast EPSCs in LA neurons were depressed < or =24 hr after ischemia. The concentration-response curves generated by application of exogenous glutamate in these neurons were approximately the same before and after ischemia. A train of five stimuli (100 Hz) induced progressively smaller EPSCs, but the proportion of decrease in EPSC amplitude at 4 hr after ischemia was significantly smaller compared with control and at 24 hr after ischemia. Parallel depression of NMDA receptor and AMPA receptor-mediated EPSCs was also observed after ischemia, supporting the involvement of presynaptic mechanisms. The adenosine A1 receptor antagonist 8-cyclopentyl-1,3-dipropylxanthine blocked the inhibition of evoked EPSCs at 4 hr after ischemia but not at 24 hr after ischemia. Electron microscopic studies demonstrated that the most presynaptic terminals in the striatum had a normal appearance at 4 hr after ischemia but showed degenerating signs at 24 hr after ischemia. These results indicated that the excitatory neurotransmission in LA neurons was depressed after ischemia via presynaptic mechanisms. The depression of EPSCs shortly after ischemia might be attributable to the enhanced adenosine A1 receptor function on synaptic transmission, and the depression at late time points might result from the degeneration of presynaptic terminals.

M Channel KCNQ2 Subunits Are Localized to Key Sites for Control of Neuronal Network Oscillations and Synchronization in Mouse Brain

Mutations in the potassium channel subunit KCNQ2 lead to benign familial neonatal convulsions, a dominantly inherited form of generalized epilepsy. In heterologous cells, KCNQ2 expression yields voltage-gated potassium channels that activate slowly (tau, approximately 0.1 sec) at subthreshold membrane potentials. KCNQ2 associates with KCNQ3, a homolog, to form heteromeric channels responsible for the M current (I(M)) in superior cervical ganglion (SCG) neurons. Muscarinic acetylcholine and peptidergic receptors inhibit SCG I(M), causing slow EPSPs and enhancing excitability. Here, we use KCNQ2N antibodies, directed against a conserved N-terminal portion of the KCNQ2 polypeptide, to localize KCNQ2-containing channels throughout mouse brain. We show that KCNQ2N immunoreactivity, although widespread, is particularly concentrated at key sites for control of rhythmic neuronal activity and synchronization. In the basal ganglia, we find KCNQ2N immunoreactivity on somata of dopaminergic and parvalbumin (PV)-positive (presumed GABAergic) cells of the substantia nigra, cholinergic large aspiny neurons of the striatum, and GABAergic and cholinergic neurons of the globus pallidus. In the septum, GABAergic, purinergic, and cholinergic neurons that contribute to the septohippocampal and septohabenular pathways exhibit somatic KCNQ2 labeling. In the thalamus, GABAergic nucleus reticularis neurons that regulate thalamocortical oscillations show strong labeling. In the hippocampus, many PV-positive and additional PV-negative interneurons exhibit strong somatic staining, but labeling of pyramidal and dentate granule somata is weak. There is strong neuropil staining in many regions. In some instances, notably the hippocampal mossy fibers, evidence indicates this neuropil staining is presynaptic.

Role of Tonically Active Neurons in Primate Caudate in Reward-Oriented Saccadic Eye Movement

Recent studies have suggested that the basal ganglia are essential for reward-oriented behavior. A popular proposal is that the interaction between sensorimotor and reward-related signals occurs in the striatal projection neurons. However, the role of interneurons remains unclear. Using the one-direction-rewarded version of the memory-guided saccade task (1DR), we examined the activity of tonically active neurons (TANs), presumed cholinergic interneurons, in the caudate. Many TANs (73/155, 47.1%) responded, usually with a pause, to a visual cue that indicated both the saccade goal and the presence or absence of reward. For most TANs (44/73, 60.3%), the response was spatially selective (contralateral dominant), but was not modulated by the reward significance. TANs are thus distinct from caudate projection neurons, which have responses to the cue that are both spatially selective and reward contingent, and from midbrain dopamine neurons, which have cue responses that are spatially nonselective and reward contingent. TANs were nonetheless sensitive to the reward schedule: in the all-directions-rewarded version (ADR) compared with 1DR, the cue responses of TANs were smaller, less frequent, and less spatially selective. In 1DR, it would first be detected that reward is not given regularly, and this process would then promote discrimination of individual stimuli in relation to reward. We propose that TANs would contribute to the detection of the context that requires discrimination, whereas dopamine neurons would contribute to the stimulus discrimination. These features of TANs might be explained by their cytoarchitecture, namely, as large aspiny neurons.

GABA(A) receptors in the primate basal ganglia: an autoradiographic and a light and electron microscopic immunohistochemical study of the alpha1 and beta2,3 subunits in the baboon brain.

The distribution of gamma-aminobutyric acid(A) (GABA(A)) receptors was investigated in the basal ganglia in the baboon brain by using receptor autoradiography and the immunohistochemical localisation of the alpha1 and beta2,3 subunits of the GABA(A) receptor by light and electron microscopy. In the caudate-putamen, the alpha1 subunit was distributed in high densities in the matrix compartment, and the beta2,3 subunits were more homogeneously distributed; the globus pallidus showed lower levels of the alpha1 and beta2,3 subunits. Four types of alpha1 subunit immunoreactive neurons were identified in the baboon striatum: the most numerous (75%) were type 1 medium-sized aspiny neurons; type 2 (2%) were large aspiny neurons with an indented nuclear membrane located in the ventral striatum; type 3 neurons were the least numerous (1%) and were comprised of large neurons in the ventromedial regions of the striatum; and type 4 (22%) neurons were medium to large aspiny neurons located in striosomes. At the ultrastructural level, alpha1 and beta2,3 subunit immunoreactivity was localised in the neuropil of the striatum in both symmetrical and asymmetrical synaptic contacts. In the globus pallidus, alpha1 and beta2,3 subunits were localised on large neurons and were found in three types of synaptic terminals: type 1 terminals were small and established symmetrical synapses; type 2 terminals were large; and type 3 terminals formed small synaptic terminals with subjunctional dense bodies. These results show that the subunit composition of GABA(A) receptors varies between the striosome and the matrix compartments in the striatum and that there is receptor subunit homogeneity in the globus pallidus.

Dopamine D1-Like Receptor Activation Excites Rat Striatal Large Aspiny NeuronsIn Vitro

The aim of this study was to elucidate electrophysiologically the actions of dopamine and SKF38393, a D1-like dopamine receptor agonist, on the membrane excitability of striatal large aspiny neurons (cholinergic interneurons). Whole-cell and perforated patch-clamp recordings were made of striatal cholinergic neurons in rat brain slice preparations. Bath application of dopamine (1-100 microM) evoked a depolarization/inward current with an increase, a decrease, or no change in membrane conductance in a dose-dependent manner. This effect was antagonized by SCH23390, a D1-like dopamine receptor antagonist. The current-voltage relationships of the dopamine-induced current determined in 23 cells suggested two conductances. In 10 cells the current reversed at -94 mV, approximately equal to the K+ equilibrium potential (EK); in three cells the I-V curves remained parallel, whereas in 10 cells the current reversed at -42 mV, which suggested an involvement of a cation permeable channel. Change in external K+ concentration shifted the reversal potential as expected for Ek in low Na+ solution. The current observed in 2 mM Ba2+-containing solution reversed at -28 mV. These actions of dopamine were mimicked by application of SKF38393 (1-50 microM) or forskolin (10 microM), an adenylyl cyclase activator, and were blocked by SCH23390 (10 microM) or SQ22536 (300 microM), an inhibitor of adenylyl cyclase. These data indicate, first, that dopamine depolarizes the striatal large aspiny neurons by a D1-mediated suppression of resting K+ conductance and an opening of a nonselective cation channel and, second, that both mechanisms are mediated by an adenylyl cyclase-dependent pathway.

Actions of Substance P on Rat Neostriatal NeuronsIn Vitro

Actions of substance P (SP) on the neostriatal neurons in in vitro rat slice preparations were studied via whole-cell patch-clamp recording. Almost all large aspiny neurons (cholinergic cells) and half of the low-threshold spike (LTS) cells (somatostatin/ NOS-positive cells) showed depolarization or an inward shift of the holding currents in response to bath-applied SP in a dose-dependent manner. In contrast, no responses were observed in fast-spiking (FS) cells (parvalbumin-positive cells) and medium spiny cells. Spike discharges followed by slow EPSPs/EPSCs were evoked by intrastriatal electrical stimulation in the large aspiny neurons. Pretreatment with [D-Arg1, D-Pro2, D-Trp7,9, Leu11]-SP, an antagonist of the SP receptor, reversibly suppressed the induction of the slow EPSPs/EPSCs and unmasked slow IPSCs. The SP-induced inward current, although almost unchanged even after the blockade of Ih channels and voltage-dependent Na+, Ca2+, and K+ channels, changed its amplitude according to the Na+ concentration used in both the large aspiny neurons and LTS cells. Thus, the cation current could account for virtually all of the inward current at resting levels in both neurons. These results suggest that the firing of afferent neurons such as striatonigral medium spiny neurons, one of the possible sources of SP, would increase the firing probability of the two types of interneurons of the neostriatum by SP-receptor-mediated opening of tetrodotoxin-insensitive cation channels.

Regional, cellular, and subcellular variations in the distribution of D1 and D5 dopamine receptors in primate brain

The pathways governing signal transduction in the mesocortical and nigrostriatal dopamine systems of the brain are of central importance in a variety of drug actions and neurological diseases. We have analyzed the regional, cellular, and subcellular distribution of the closely related D1 and D5 subtypes of dopamine receptors in the cerebral cortex and selected subcortical structures of rhesus monkey using subtype specific antibodies. The distribution of D1 and D5 receptors was highly differentiated in subcortical structures. In the neostriatum, both D1 and to a lesser extent D5 antibodies labeled medium spiny neurons, while only D5 antibodies labeled the large aspiny neurons typical of cholinergic interneurons. In the caudate nucleus, D1 labeling was concentrated in the spines and shafts of projection neurons, whereas D5 antibodies predominantly labeled the shafts, and less commonly, the spines of these cells. The D1 receptor was abundantly expressed in the neuropil of the substantia nigra pars reticulata while the D5 antibodies labeled only a few scattered cell bodies in this structure. Conversely, D5 antibodies labeled cholinergic neurons in the basal forebrain more intensely than D1 antibodies. Within the cerebral cortex and hippocampus, D1 and D5 antibody labeling was prominent in pyramidal cells. Double-label experiments revealed that the two receptors were frequently coexpressed in neurons of both structures. Ultrastructurally, D1 receptors were especially prominent in dendritic spines whereas dendritic shafts were more prominently labeled by the D5 receptor. The anatomical segregation of the D1 and D5 receptors at the subcellular level in cerebral cortex and at the cellular level in subcortical areas suggest that these closely related receptors may be preferentially associated with different circuit elements and may play distinct regulatory roles in synaptic transmission.

Large aspiny cells in the matrix of the rat neostriatum in vitro: physiological identification, relation to the compartments and excitatory postsynaptic currents.

1. Large aspiny neurons (20-60 microns diam) in the neostriatum were studied in an in vitro rat slice preparation by whole-cell recording to reveal physiological identification from medium-sized spiny projection cells (10-20 microns diam), relation to the patch and matrix compartments, and excitatory synaptic inputs. Recorded cells were identified by intracellular biocytin staining. Compartmental identification was made by calbindinD28K immunohistochemistry in fixed slices. 2. Large stained neurons were morphologically heterogeneous and had aspiny or sparsely spiny dendrites and dense local axonal branches. They were located in the matrix or on the patch-matrix border. Axonal branches of the large aspiny cells were preferentially distributed in the matrix and gave off terminal boutons there. Some of the secondary dendrites arising from stem dendrites running along the border, however, crossed compartment boundaries and made fine branches in a patch. 3. Large aspiny cells had less negative resting membrane potentials and lower thresholds for spike generation than medium spiny cells. They showed longer-duration and larger-amplitude afterhyperpolarizations (AHPs) than medium spiny cells. During hyperpolarizing current pulses, apparent resistance slowly reduced, and a prominent sag was observed in the voltage record, which was absent in medium spiny cells. The large aspiny cells showed no spontaneous firing but had a tendency to fire repetitive spikes in response to depolarizing current pulses, although spike interval tended to increase in later spikes. Spike frequency of large aspiny cells increased less with current intensity than that of medium spiny cells. 4. Most large aspiny cells were considered to belong to a single physiological class, although one large aspiny cells showed shorter-duration AHPs than both most other large aspiny cells and medium spiny cells, and little spike-frequency adaptation. 5. Excitatory postsynaptic currents (EPSCs) of large aspiny cells induced by intrastriatal stimulation had two components. An early, linear component was blocked by 10 microM 6-cyano-7-nitro-quinoxaline-2,3-dione (CNQX), a selective antagonist of non-N-methyl-D-aspartate (NMDA) receptors. A later component with a nonlinear current-voltage (I-V) relationship was blocked by 50 microM DL-2-amino-5-phosphonovaleric acid (DL-APV), a selective antagonist of NMDA receptors. 6. From these results, four conclusions can be drawn. 1) Most large aspiny neostriatal cells in the matrix, although they take heterogeneous shapes, belong to one physiological class with long-duration AHPs and a strong time-dependent component of anomalous rectification.(ABSTRACT TRUNCATED AT 400 WORDS)

Nitric oxide synthase and neuronal NADPH diaphorase are identical in brain and peripheral tissues.

NADPH diaphorase staining neurons, uniquely resistant to toxic insults and neurodegenerative disorders, have been colocalized with neurons in the brain and peripheral tissue containing nitric oxide synthase (EC 1.14.23.-), which generates nitric oxide (NO), a recently identified neuronal messenger molecule. In the corpus striatum and cerebral cortex, NO synthase immunoreactivity and NADPH diaphorase staining are colocalized in medium to large aspiny neurons. These same neurons colocalize with somatostatin and neuropeptide Y immunoreactivity. NO synthase immunoreactivity and NADPH diaphorase staining are colocalized in the pedunculopontine nucleus with choline acetyltransferase-containing cells and are also colocalized in amacrine cells of the inner nuclear layer and ganglion cells of the retina, myenteric plexus neurons of the intestine, and ganglion cells of the adrenal medulla. Transfection of human kidney cells with NO synthase cDNA elicits NADPH diaphorase staining. The ratio of NO synthase to NADPH diaphorase staining in the transfected cells is the same as in neurons, indicating that NO synthase fully accounts for observed NADPH staining. The identity of neuronal NO synthase and NADPH diaphorase suggests a role for NO in modulating neurotoxicity.

Sparing of acetylcholinesterase-containing striatal neurons in Huntington's disease

The present study demonstrates that large aspiny neurons, containing the enzyme acetylcholinesterase (AChE), are relatively preserved in the caudate nucleus and putamen in Huntington's disease (HD). Although histochemical evidence indicates that AChE and choline acetyltransferase (ChAT) co-localize within the same striatal neurons, measurements of ChAT activity showed significant reductions in enzyme activity, as others have reported. Reduced ChAT activity in the presence of persistent AChE-positive neurons may be a consequence of loss of synaptic terminals resulting from the death of spiny neurons. The selectivity of neuronal sparing in HD may be related to the patterns of synaptic contact or a paucity of excitatory amino acid receptors on striatal aspiny neurons.

Characterization of fimbria input to nucleus accumbens

The hippocampal input to the nucleus accumbens was studied by correlative electrophysiological and anatomical techniques in acutely prepared rabbits. Field and extracellular unitary potentials were recorded in the nucleus accumbens following ipsilateral fimbria stimulation. Analysis of the components of the field response was based on the relevant correlations with extracellular unitary activity. The cellular types that are the recipients of the hippocampal projection were determined by combined intracellular horseradish peroxidase (HRP) and Golgi analyses. The distribution of the hippocampal input was determined by combined field potential and current source density analyses. It was found that the ipsilateral fimbria projection was distributed to the dorsal two-thirds of the nucleus, with the projection being heaviest in the more caudal portions of the nucleus. The negative (N) component of the field response was studied by correlating its behavior with the appropriate extracellular unitary recordings. It was concluded that the N-component represented an envelope of monosynaptically activated action potentials. The positive (P) component of the field response throughout the nucleus accumbens was studied pharmacologically with the iontophoretic administration of bicuculline. The P-components, in both the dorsal and ventral regions of the nucleus, were diminished by bicuculline application, indicating that this potential results from the activation of gamma-aminobutyric acid (GABA) mechanisms. The cell populations that are the targets for the hippocampal projections were studied by the technique of intracellular staining with HRP. These results were correlated with the findings of a Golgi analysis. Two distinct cell types were found to respond in a monosynaptic manner to ipsilateral fimbria stimulation. The most common of the two were the small-to medium-sized spiny neurons, and they were distributed throughout the nucleus. These cells have a spherical dendritic arrangement. The second, and most distinctive, of the cell types were the large aspiny neurons. These cells were distributed medially and caudally in the nucleus. Two of the outstanding features of these cells were the expanse of their dendritic domains and the fact that axons originated from relatively remote portions of the dendrites.