Long-term Depression Requires Nitric Oxide and Guanosine 3':5'Cyclic Monophosphate Production in Rat Cerebellar Purkinje Cells

In patch-clamped Purkinje cells, bath application of the nitric oxide synthase inhibitor N _G-methyl- l -arginine consistently prevents the induction of long-term depression (LTD) of parallel fibre-mediated excitatory postsynaptic potentials (EPSPs) induced by their pairing with calcium spikes. On the other hand, bath application of nitric oxide donors and of 8-bromoguanosine 3':5'cyclic monophosphate is able to reproduce an LTD-like phenomenon. LTD of parallel fibre-mediated EPSPs also occurs when nitric oxide donors or guanosine 3':5'cyclic monophosphate are directly dialysed into Purkinje cells, and this effect partially occludes LTD induced by pairing protocols. These results show that nitric oxide does play a role in LTD induction, and demonstrate for the first time that its site of action is probably the soluble guanylate cyclase of Purkinje cells.     

Receptors and Second Messengers Involved in Long-term Depression in Rat Cerebellar Slices In Vitro: a Reappraisal

In patch-clamped Purkinje cells (PCs), bath application of the ionotropic glutamate receptor antagonist, 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) prevents induction of long-term depression (LTD) of parallel fibre (PF)-mediated EPSPs by a pairing protocol between Ca²⁺ spike firing and PF stimulation whereas bath application of ( RS )-α-methyl-4-carboxyphenylglycine (MCPG), a metabotropic glutamate (mGLU) receptor antagonist, does not. On the other hand, LTD can be also induced by pairing direct depolarization of PCs with activation of mGLU receptors by 1 S,3 R -aminocyclopentyl-dicarboxylate (1S, 3 R -ACPD), even in the presence of CNQX. In this case, LTD induction is not consistently blocked by bath application of the nitric oxide synthase inhibitor, N _G-methyl- l -arginine ( l -NMMA), whereas it is strongly blocked when the protein kinase C inhibitor peptide 19-36 is dialysed into PCs. These results are at variance with LTD induced by a pairing protocol between Ca²⁺ spikes and PF-mediated EPSPs which depends to the same extent on both cascades. Finally, thapsigargin, which depletes most intracellular Ca²⁺ pools, does not block induction of LTD by a pairing protocol between Ca²⁺ spikes and PF-mediated EPSPs whereas it prevents the induction of LTD depending on strong mGLU receptor activation.     

Long-term Depression in the Hippocampal CA1 Region is Associated with Equal Changes in AMPA and NMDA Receptor-mediated Synaptic Potentials

In the CA1 hippocampal region low-frequency (1-2 Hz) afferent activation leads to a long-term depression of excitatory synaptic potentials that is induced by calcium influx through postsynaptic N -methyl- d -aspartate receptor channels. In the present experiments using 2- to 3-week-old rats, long-term depressions of field excitatory postsynaptic potentials mediated by amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and by N -methyl- d -aspartate receptor channels were examined in parallel, using a perfusion solution containing low concentrations of an AMPA receptor antagonist and of magnesium (0.1 mM). These experiments revealed that long-term depression was associated with equal relative changes in the two components of the field potential, compatible with a presynaptic location of the expression mechanism for the long-term depression.     

Long-term Depression of Horizontal Connections in Rat Motor Cortex

The possibility for long-term depression (LTD) of synaptic transmission in layer 11/11 I horizontal connections within motor cortex was investigated using field potentials and intracellular recordings in rat brain slices. The LTD was induced by low-frequency stimulation at 2 Hz for 10 min in sites displaced horizontally by 0.5 mm from the stimulating electrode. Response amplitude measured 25-30 min after 2 Hz stimulation ended was 79% of baseline values ( n = 13) at half maximal stimulation and 59% when 2 Hz stimulus intensity was doubled ( n = 10). In 13/15 tested cases LTD in horizontal connections was specific to the activated pathway. Intracellular recordings from six neurons confirmed synaptic character of response depression. Horizontal connections in which LTD was induced retained the capability of increasing synaptic strength. Long-term potentiation could be induced in previously depressed pathways by simultaneous theta burst stimulation of two converging horizontal inputs combined with transient local application of GABAA receptor antagonist bicuculline methiodide (mean increase: 45 ± 8%, n = 6) or by simultaneous theta burst stimulation of converging horizontal and vertical inputs (mean change: 26 5 6%, n = 5). These data demonstrate that activity-dependent mechanisms may regulate bidirectionally the effectiveness of horizontal synaptic coupling between cortical neurons, thus forming a potential mechanism for plasticity of cortical connections and the representation patterns they support.     

Transient Sensitivity of Rat Cerebellar Purkinje Cells to N-methyl-D-aspartate during Development. A Voltage Clamp Study in in vitro Slices

In vitro sagittal slices of immature rat cerebellum were used to study the development of the sensitivity of Purkinje cells (PC) to L-glutamate (Glu) and N-methyl-D-aspartate (NMDA). In 8-day-old animals, all PCs recorded in magnesium-free medium responded to iontophoretic applications of both agonists by transient and dose dependent inward currents which, in both cases, were heavily contaminated by a Glu and NMDA-induced synaptic noise. When 5 x 10-6 M tetrodotoxin (TTX) was added to the perfusing medium, this evoked synaptic noise was completely abolished in most cells whereas clear-cut inward currents induced in PCs by Glu and NMDA applications on their dendrites were still visible. These responses were selectively antagonized by the non-NMDA glutamate receptor antagonist 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) and by the NMDA receptor antagonist D-2-aminophosphono-5-valeric acid (2APV) respectively. Excitatory responses induced by aspartate in 8 - 10-day-old PCs were also markedly antagonized by CNQX. At this stage, the sensitivity of PCs to NMDA was about one order of magnitude less than that to Glu. In 15 - 20-day-old animals, all PCs were still responsive to Glu whereas only 70% of them were still excited by NMDA in the presence of TTX in the bath. Furthermore, the sensitivity of PCs to Glu was higher than at 8 days of age, whereas that to NMDA was significantly lower, even when considering only those cells which still responded to this agonist. This trend was still accentuated later on since at 2 months of age, only 25% of PCs were excited by NMDA whereas their sensitivity to Glu was similar to that observed in 15 - 20-day-old animals. Therefore, the present results are fully consistent with the view that PCs have a transient expression of NMDA receptors during development.     

Simultaneous Expression of Long-term Depression of NMDA and Long-term Potentiation of AMPA Receptor-mediated Synaptic Responses in the CA1 Area of the Kainic Acid-lesioned Hippocampus

This study investigates the plasticity of the excitatory synapses in an experimental model of epilepsy, the kainic acid-lesioned rat hippocampus. Stimulation of afferents in the CA1 area of lesioned hippocampi produced an epileptiform burst of action potentials, with an underlying synaptic potential composed of mixed α-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA; 80%) and N -methyl-D-aspartate (NMDA; 20%) receptor-mediated components. Tetanic stimulation yielded a long-term potentiation (LTP) of the mixed AMPA/NMDA receptor-mediated population excitatory postsynaptic potentials. However, the same type of tetanus resulted in a long-term depression (LTD) of pharmacologically isolated NMDA receptor-mediated responses. This LTD occurred independently of the antagonism of AMPA receptors. This suggests that tetanic stimulation produced LTP of AMPA and LTD of NMDA receptor-mediated responses simultaneously. Finally, both LTP and LTD were shown to be NMDA dependent. This property has profound functional implications for the control of excitatory networks in temporal lobe epilepsy. This work was supported by the Wellcome Trust and the Fondation Simone et Cino Del Duca.     

Microinfusion of the Metabotropic Glutamate Receptor Agonist 1S, 3R–1-Aminocyclopentane-1, 3-dicarboxylic Acid Into the Nucleus Accumbens Induces Dopamine-dependent Locomotor Activation in the Rat

Although the striatum has one of the highest densities of metabotropic glutamate receptor (mGluR) binding sites in the brain, little is known about their physiological role. In this study we characterized the contribution of mGluRs located in the ventral part of the striatum (the nucleus accumbens) to the control of extrapyramidal motor function. Activation of mGluRs by local infusion of the selective agonist 1S, 3R–1-aminocyclopentane-1, 3-dicarboxylic acid (1 S, 3R-ACPD; 25, 50 and 100 nmol/0.5 μl) into the nucleus accumbens induced a dose-dependent increase in locomotor activity in rats. Intra-accumbens infusion of a selective antagonist of mGluRs, a-methyl-4-carboxyphenylglycine (MCPG) did not modify spontaneous locomotion but decreased the locomotor response to 1S, 3R-ACPD. This effect appeared to be mediated by dopamine, since blockade of dopamine receptors with haloperidol (0.05 and 0.1 mg/kg i.p.) dose-dependently reduced 1 S3R-ACPD-induced locomotor activation. Furthermore, D-amphetamine (0.5 mg/kg, i.p.) combined with intra-accumbens infusion of 1S, 3R-ACPD (100 nmol) potentiated the locomotor hyperactivity response to a higher level than that seen with a single treatment with either drug. In contrast, D-amphetamine-induced hypermotility was abolished by infusion of MCPG (100 nmol) into the nucleus accumbens. These results demonstrate that glutamate may control extrapyramidal motor function through metabotropic receptors. Furthermore, activation of metabotropic glutamate receptors appears to act in synergy with the dopamine system at the level of the nucleus accumbens to produce a motor stimulant response.     

Aspartate- and Glutamate-like Immunoreactivities in Rat Hippocampal Slices: Depolarization-induced Redistribution and Effects of Precursors

The light microscopic localization of aspartate-like immunoreactivity (Asp-LI) was compared to that of glutamate-like immunoreactivity (Glu-LI) in hippocampal slices by means of specific polyclonal antibodies recognizing the amino acids fixed by glutaraldehyde. After incubation in Krebs' solution with normal (5 mM) or depolarizing concentrations of K+, and various additives, the slices were fixed with glutaraldehyde, resectioned and processed according to the peroxidase - antiperoxidase procedure. At 5 mM K+, Glu-LI was localized in nerve-terminal like dots with a conspicuous laminar distribution, the highest Glu-LI concentrations coinciding with the terminal fields of major excitatory pathways thought to use glutamate or aspartate as transmitters. The localization of Asp-LI showed some similarity to that of Glu-LI, but the laminar distribution was less differentiated and the immunoreactivity was much weaker. At 40 and 55 mM K+ the nerve terminal localizations of Glu-LI and Asp-LI were strongly reduced. Concomitantly, both immunoreactivities appeared in astroglial cells. These changes were Ca2+-dependent. The nerve ending staining patterns of Asp-LI and Glu-LI could be sustained during depolarization if the medium was supplemented with glutamine (0.5 mM). Under these conditions Asp-LI became more intense and its distribution approached that of Glu-LI. This suggests that, when stimulated, some nerve endings can increase their reservoir of releasable aspartate. The presence of glutamine during depolarization strongly reduced glial Asp-LI and Glu-LI, possibly due to its providing nitrogen for conversion of glutamate to glutamine. alpha-Ketoglutarate, another glia-derived precursor of neuronal glutamate, was virtually ineffective in supporting Glu-LI and Asp-LI in nerve endings, and did not suppress Glu-LI or Asp-LI in glia. Our findings provide morphological support for the view that excitatory nerve endings under certain conditions can contain high levels of both aspartate and glutamate (possibly in the same terminals), and that aspartate as well as glutamate can be released synaptically. Further, they underline the importance of the glial supply of the nerve endings with precursor glutamine, which allows them to build up and sustain high concentrations of transmitter amino acids during release.     

Coordinated Postnatal Maturation of Striatal Cholinergic Interneurons and Dopamine Release Dynamics in Mice

Dynamic changes in motor abilities and motivated behaviors occur during the juvenile and adolescent periods. The striatum is a subcortical nucleus critical to action selection, motor learning, and reward processing. Its tonically active cholinergic interneuron (ChI) is an integral regulator of the synaptic activity of other striatal neurons, as well as afferent axonal projections of midbrain dopamine (DA) neurons; however, little is known about its development. Here, we report that ChI spontaneous activity increases during postnatal development of male and female mice, concomitant with a decreased afterhyperpolarization (AHP). We characterized the postnatal development of four currents that contribute to the spontaneous firing rate of ChIs, including I_SK, I_A, I_h, and I_NaP. We demonstrated that the developmental increase in I_NaP drives increased ChI firing rates during the postnatal period and can be reversed by the I_NaP inhibitor, ranolazine. We next addressed whether immature cholinergic signaling may lead to functional differences in DA release during the juvenile period. In the adult striatum, nicotinic acetylcholine receptors (nAChRs) prevent linear summation of DA release in response to trains of high-frequency stimuli. We show that, in contrast, during the second postnatal week, DA release linearly sums with trains of high-frequency stimuli. Consistently, nAChR antagonists exert little effect on dopamine release at postnatal day (P)10, but enhance the summation of evoked DA release in mice older than postnatal day P28. Together, these results reveal that postnatal maturation of ChI activity is due primarily to enhanced I_NaP and identify an interaction between developing cholinergic signaling and DA neurotransmission in the juvenile striatum.SIGNIFICANCE STATEMENT Motor skills and motivated behavior develop rapidly in juvenile rodents. Recent work has highlighted processes that contribute to the postnatal maturation of striatal principal neurons during development. The functional development of the striatal cholinergic interneuron (ChI), however, has been unexplored. In this study, we tracked the ontogeny of ChI activity and cellular morphology, as well as the developmental trajectory of specific conductances that contribute to the activity of these cells. We further report a link between cholinergic signaling and dopamine (DA) release, revealing a change in the frequency-dependence of DA release during the early postnatal period that is mediated by cholinergic signaling. This study provides evidence that striatal microcircuits are dynamic during the postnatal period and that they undergo coordinated maturation.     

Ethanol reverses the direction of long-term synaptic plasticity in the dorsomedial striatum

The striatum is a critical structure for the control of voluntary behaviour, and striatal synaptic plasticity has been implicated in instrumental learning. As ethanol consumption can cause impairments in cognition, learning, and action selection, it is important to understand the effects of this drug on striatal function. In this study we examined the effects of ethanol on long-term synaptic plasticity in the dorsomedial striatum (DMS), a striatal subregion that plays a central role in the acquisition and selection of goal-directed actions. Ethanol was found to impair N-methyl-d-aspartic acid receptor (NMDAR)-dependent long-term potentiation (LTP) dose-dependently in the DMS, and to promote long-term depression (LTD) at the highest concentration (50 mm) used. These results suggest that ethanol, at a concentration usually associated with mild intoxication, could significantly change experience-dependent modification of corticostriatal circuits underlying the learning of goal-directed instrumental actions.     

Long-term potentiation in the hippocampus involves activation of N-methyl-D-aspartate receptors

A series of ω-phosphono-α-car?ylic acids were tested as antagonists of excitatory amino acid depolarizations and long-term potentiation (LTP) in region CA1 of rat hippocampal slices. The 5- and 7-phosphono compounds (±AP5and±AP7) blocked N-methyl-D-aspartate (NMDA) depolarizations and prevented the induction of LTP of the synaptic field potential and population spike components of the Schaffer collateral response.±AP5and±AP7 did not reduce kainate or quisqualate depolarizations and did not affect unpoten synaptic response amplitude.±AP5, ±AP6and±AP8 did not block amino acid excitant responses or LTP.These results demonstrate that NMDA receptors present in hippocampal region CA1 are not necessary for normal synaptic transmission, but are involved in the initiation of long-term synaptic plasticity.     

Differentially altered mGluR1 and mGluR5 mRNA expression in rat caudate nucleus and nucleus accumbens in the development and expression of behavioral sensitization to repeated amphetamine administration.

Altered glutamatergic transmission in the striatum may be implicated in behavioral sensitization to repeated amphetamine (AMPH) administration. Quantitative in situ hybridization histochemistry was performed to define the effects of acute and chronic AMPH exposures on mRNA expression of Group I metabotropic glutamate receptors (mGluRs) in the striatum. Behavioral ratings indicated that the motor activity of rats was significantly higher after the final of five daily AMPH injections (4 mg/kg, i.p.) than that after the first of five daily AMPH, indicative of the development of behavioral sensitization. Moreover, the motor activity of rats treated with five daily AMPH was significantly greater than that of rats treated with five daily saline in response to a 2 mg/kg challenge dose of AMPH 7, 14, 28, and 60 days after the discontinuation of drug treatments, indicative of the persistent expression of behavioral sensitization. Three hours after acute administration of AMPH to naive rats, mGluR1 and mGluR5 mRNA expression in the dorsal (caudatoputamen) and ventral (nucleus accumbens) striatum showed no change as compared to acute saline injection. In rats that developed behavioral sensitization to repeated AMPH, mGluR1 levels in the dorsal and ventral striatum were increased by 53% and 43%, respectively, 3 h after the final AMPH treatment. However, this change did not persist during withdrawal since it was not observed 7, 14, and 28 days after the discontinuation of AMPH treatment. Conversely, mGluR5 levels were markedly reduced 3 h after the final of five daily AMPH treatments in the entire striatum of sensitized rats (34% and 77% of controls in the dorsal and ventral striatum, respectively). The reduction persisted at 7, 14, and 28 days of withdrawal. These results reveal a close linkage between striatal Group I mGluR gene expression and behavioral sensitization to AMPH. This may indicate functional implications of the two subtypes of Group I mGluRs in the regulation of behavioral sensitization to the dopamine stimulant.     

Effects of intrastriatal cannabinoids on rotational behavior in rats: Interactions with the dopaminergic system

The effect of unilateral intrastriatal cannabinoid receptor stimulation on rotational behavior in rats was explored. The potent cannabinoid agonist CP 55,940 (5 μg/0.5 μl) induced contralateral turning when microinjected unilaterally into the striatum. The D₂dopamine agonist quinpirole reversed this contralateral rotation but failed to affect motor behavior on its own. Finally, the D₁dopamine agonist SKF 82958 inhibited movement when administered into the striatum and this inhibition was reversed by co-administration of the cannabinoid agonist. Surprisingly, microinjections of the cannabinoid agonist into the striatum induced movement through activation of the striatonigral pathway and/or inhibition of the striatopallidal pathway, while the D₁dopamine agonist produced the opposite effect. Synapse 30:221–226, 1998. © 1998 Wiley-Liss, Inc.     

Modulation of GABA-mediated Synaptic Potentials by Glutamatergic Agonists in Neonatal CA3 Rat Hippocampal Neurons

Intracellular recordings were made from slices of adult and neonatal hippocampal neurons. During the first 2 weeks of life the majority of pyramidal cells exhibited spontaneous gamma-aminobutyric acid (GABA)-mediated synaptic potentials, which were depolarizing at birth and became hyperpolarizing by the end of the first postnatal week. These synaptic potentials were reduced in frequency or blocked by the N-methyl-d-aspartate (NMDA) receptor antagonist d(-)2-amino-5-phosphonovalerate (AP-5, 50 microM) (13/15 cells). The non-NMDA antagonist, 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX, 5 - 10 microM) abolished the GABA-mediated synaptic potentials in all the cells tested (n=12), Superfusion of l-glutamate (up to 100 microM) increased the frequency of both depolarizing and hyperpolarizing GABA-mediated synaptic potentials. This effect was reduced by AP-5 or dl-2-amino-7-phosphonoheptanoate (AP-7, 50 microM) and fully blocked by concomitant application of AP-5 (50 microM) and CNQX (5 - 10 microM). NMDA (0.5 - 2 microM) increased the frequency of the GABA-mediated synaptic potentials. These effects were blocked by AP-5 (50 microM) and by bicuculline (10 microM). Quisqualate (100 - 300 nM), (RS)-alpha-amino-3-hydroxy-5-methyl-4-izopropionate (AMPA, 100 - 300 nM) and kainate (100 nM) also increased the frequency of the GABA-mediated synaptic potentials. These effects were blocked by CNQX (5 - 10 microM) and by bicuculline (10 microM) but not by AP-5 (50 microM). In the presence of tetrodotoxin (TTX, 1 microM), quisqualate (up to 300 nM), AMPA (up to 500 nM) and kainate (100 nM) had no effect on membrane potential or input resistance. In conclusion, our experiments suggest that, in early postnatal life, NMDA and non-NMDA receptors located on GABAergic interneurons modulate GABAergic synaptic potentials.     

Reward-guided learning beyond dopamine in the nucleus accumbens: the integrative functions of cortico-basal ganglia networks

Here we challenge the view that reward-guided learning is solely controlled by the mesoaccumbens pathway arising from dopaminergic neurons in the ventral tegmental area and projecting to the nucleus accumbens. This widely accepted view assumes that reward is a monolithic concept, but recent work has suggested otherwise. It now appears that, in reward-guided learning, the functions of ventral and dorsal striata, and the cortico-basal ganglia circuitry associated with them, can be dissociated. Whereas the nucleus accumbens is necessary for the acquisition and expression of certain appetitive Pavlovian responses and contributes to the motivational control of instrumental performance, the dorsal striatum is necessary for the acquisition and expression of instrumental actions. Such findings suggest the existence of multiple independent yet interacting functional systems that are implemented in iterating and hierarchically organized cortico-basal ganglia networks engaged in appetitive behaviors ranging from Pavlovian approach responses to goal-directed instrumental actions controlled by action-outcome contingencies.     

Aberrant striatal plasticity is specifically associated with dyskinesia following levodopa treatment

Chronic levodopa treatment for Parkinson's disease often results in the development of abnormal involuntary movement, known as L ‐dopa‐induced dyskinesia (LIDs). Studies suggest that LIDs may be associated with aberrant corticostriatal plasticity. Using in vivo extracellular recordings from identified Type I and Type II medium spiny striatal neurons, chronic L ‐dopa treatment was found to produce abnormal corticostriatal information processing. Specifically, after chronic L ‐dopa treatment in dopamine‐depleted rats, there was a transition from a cortically evoked long‐term depression (LTD) to a complementary but opposing form of plasticity, long‐term potentiation, in Type II “indirect” pathway neurons. In contrast, LTD could still be induced in Type I neurons. Interestingly, the one parameter that correlated best with dyskinesias was the inability to de‐depress established LTD in Type I medium spiny striatal neurons. Taken as a whole, we propose that the induction of LIDs is due, at least in part, to an aberrant induction of plasticity within the Type II indirect pathway neurons combined with an inability to de‐depress established plastic responses in Type I neurons. Such information is critical for understanding the cellular mechanisms underlying one of the major caveats to L ‐dopa therapy. © 2010 Movement Disorder Society     

Synaptic coexistence of AMPA and NMDA receptors in the rat hippocampus: A postembedding immunogold study

Synaptic distributions of N-methyl-d -aspartate (NMDA) and α-amino-3-hydroxy-5-methylisoxazolepropionic acid (AMPA) receptor subunits, NMDAR1 and GluR2, respectively, were examined by electron microscopy with the high spatial resolution of postembedding immunogold localization. We provide direct evidence for colocalization at individual axodendritic asymmetric synapses within the CA1 subfield of rat hippocampus. AMPA/ NMDA receptor colocalization was found both in γ-aminobutyric acid (GABA)ergic dendrites and non-GABAergic dendritic shafts, as well as dendritic spines. Some asymmetric synapses were found to contain only NMDAR1 or GluR2; however, most immunopositive synapses contained both subunits. Many NMDAR1 and/ or GluR2 immunopositive profiles received GABAergic innervation at an adjacent synapse, providing a substrate for GABAergic modulation of both GluR classes. These data suggest that excitatory neuronal transmission in CA1 neurons may generally involve activation of both NMDA and AMPA receptor subunits at a single synapse, however, they also offer ultrastructural evidence for NMDAR1-only synapses that might represent silent synapses. J. Neurosci. Res. 54:444–449, 1998. © 1998 Wiley-Liss, Inc.     

Morphological Changes in Met5-enkephalin-immunoreactive Synaptic Boutons in the Rat Neostriatum after Haloperidol Decanoate Treatment

The morphological plasticity of an identified population of synaptic boutons in the rat neostriatum was investigated 24 h (short-term treatment) or 14 days (long-term treatment) after administration of the depot neuroleptic, haloperidol decanoate. Specific methionine⁵-enkephalin antiserum was used to label bouton profiles in the dorsal neostriatum. The size and shape of these boutons was subsequently analysed with quantitative methods at the ultrastructural level. Immunoreactive synaptic bouton profiles were found to have a larger cross-sectional area, to be less circular in shape and to have a longer maximum diameter after long-term neuroleptic treatment. These parameters were not significantly affected by short-term neuroleptic treatment. The morphological parameters indicate that methionine⁵-enkephalin-immunoreactive boutons become enlarged, probably by elongating. This suggests that boutons containing methionine⁵-enkephalin increase their potential synaptic efficacy in the long term after neuroleptic treatment.     

Dopaminergic regulation of glutamic acid decarboxylase mRNA expression and GABA release in the striatum: A review

Lindefors Nils: Dopaminergic Regulation of Glutamic Acid Decarboxylase mRNA Expression and GABA Release In the Striatum: A Minireview. Prog. Neuro-Psychopharmacol. & Biol. Psychiat. 1993, 17(6): 887–903.

1. 1. The majority of neurons in the striatum (caudate-putamen, dorsal striatum; nucleus accumbens, ventral striatum) and in striatal projection regions (the pallidum, the entopeduncular nucleus and substantia nigra reticulata) use γ-aminobuturic acid (GABA) as transmitter and express glutamic acid decarboxylase (GAD; rate limiting enzyme) in the synthesis of GABA. GABA is the major inhibitory transmitter in the mammlian brain.

2. 2. GAD in brain is present as two isoenzymes, GAD₆₅ and GAD₆₇. GAD₆₅ is largely present as an inactive apoenzyme, which can be induced by nerve activity, while most GAD₆₇ is present as a pyridoxal phosphate-bound permanently active holoenzyme. Thus GAD₆₅ and GAD₆₇ seem to provide a dual system for the control of neuronal GABA synthesis.

3. 3. GAD mRNA expression can be visualised and quantified using in situ hybridisation, and GABA release can be quantified using in vivo microdialysis.

4. 4. Different populations of GABA neurons can be distinguished in both dorsal and ventral striatum as well as in other parts of the basal ganglia.

5. 5. Inhibition of dopaminergic transmission in the striatum by lesion of dopamine neurons or by neuroleptic treatment is followed by an increased release of GABA and increased expression of GAD₆₇ mRNA in a subpopulation of striatal medium-sized neurons which project to the globus pallidus, and increased striatal GAD enzyme activity.

6. 6. Increased dopaminergic transmission by repeated but not single doses of amphetamine is followed by decreased striatal GABA release and decreased GAD₆₇ mRNA expression in a subpopulation of medium-sized neurons in the striatum.

7. 7. Two populations of medium-sized GABA neurons in the striatum seem to be under tonic dopaminergic influence. The majority of these GABA neurons are under inhibitory influence, whereas a small number seem to be stimulated by dopamine.

8. 8. Specific changes in activity in subpopulations of striatal GABA neurons probably mediate the dopamine-dependent hypokinetic syndrome seen in Parkinson's disease and following neuroleptic treatment.

Long-term potentiation in the hippocampus involves activation of N-methyl-D-aspartate receptors

A series of ω-phosphono-α-car☐ylic acids were tested as antagonists of excitatory amino acid depolarizations and long-term potentiation (LTP) in region CA1 of rat hippocampal slices. The 5- and 7-phosphono compounds (±AP5and±AP7) blocked N-methyl-D-aspartate (NMDA) depolarizations and prevented the induction of LTP of the synaptic field potential and population spike components of the Schaffer collateral response.±AP5and±AP7 did not reduce kainate or quisqualate depolarizations and did not affect unpoten synaptic response amplitude.±AP5, ±AP6and±AP8 did not block amino acid excitant responses or LTP.These results demonstrate that NMDA receptors present in hippocampal region CA1 are not necessary for normal synaptic transmission, but are involved in the initiation of long-term synaptic plasticity.