Spiny Projection Neurons In Striatum Research Articles

Neurogliaform cells of amygdala: a source of slow phasic inhibition in the basolateral complex

Synaptic inhibition in the amygdala actively participates in processing emotional information. To improve the understanding of interneurons in amygdala networks it is necessary to characterize the GABAergic cell types, their connectivity and physiological roles. We used a mouse line expressing a green fluorescent protein (GFP) under the neuropeptide Y (NPY) promoter. Paired recordings between presynaptic NPY-GFP-expressing (+) cells and postsynaptic principal neurons (PNs) of the basolateral amygdala (BLA) were performed. The NPY-GFP+ neurons displayed small somata and short dendrites embedded in a cloud of highly arborized axon, suggesting a neurogliaform cell (NGFC) type. We discovered that a NPY-GFP+ cell evoked a GABA(A) receptor-mediated slow inhibitory postsynaptic current (IPSC) in a PN and an autaptic IPSC. The slow kinetics of these IPSCs was likely caused by the low concentration and spillover of extracellular GABA. We also report that NGFCs of the BLA fired action potentials phase-locked to hippocampal theta oscillations in anaesthetized rats. When this firing was re-played in NPY+-NGFCs in vitro, it evoked a transient depression of the IPSCs. Presynaptic GABA(B) receptors and functional depletion of synaptic vesicles determined this short-term plasticity. Synaptic contacts made by recorded NGFCs showed close appositions, and rarely identifiable classical synaptic structures. Thus, we report here a novel interneuron type of the amygdala that generates volume transmission of GABA. The peculiar functional mode of NGFCs makes them unique amongst all GABAergic cell types of the amygdala identified so far.

Somatostatin in Medium-Sized Aspiny Interneurons of Striatum is Responsible for Their Preservation in Quinolinic Acid and N-Methyl-d-Asparate-Induced Neurotoxicity

Somatostatin (SST) is a multifunctional peptide and involves in several neurodegenerative diseases. N-Methyl-D-asparate (NMDA) receptor agonist quinolinic acid (QUIN)-induced neurotoxicity mimics an experimental model of Huntington's disease that is characterized by the selective preservation of medium-sized aspiny interneurons and degeneration of medium-sized spiny projection neurons in striatum. In QUIN- and NMDA-induced neurotoxicity, increased expression of SST and messenger RNA levels along with SST release in culture medium is generally observed. However, the molecular mechanisms and the functional consequences of increased SST are still obscure. In the present study, the role of SST was determined using immunoneutralization and immunoblockade of SST in cultured striatal neurons upon QUIN- and NMDA-induced neurotoxicity. The immunoblockade of SST with antisense oligonucleotides and immunoabsorption of released SST with specific antibodies potentiate QUIN- and NMDA-induced neuronal cell death. NADPH-diaphorase positive neurons that are selectively spared in several processes of neurodegeneration result in severe damage upon immunoblockade or immunoabsorption of SST. In addition, exogenous SST along with QUIN and NMDA provides selective preservation of projection neurons, which are selectively susceptible in excitotoxicity. Neuroprotective effect of SST is completely blocked by pertussis toxins, suggesting the role of somatostatin receptors. Taken together, these results provide first evidence that the presence of SST is a unique feature for the selective sparing of medium sized aspiny interneurons in excitotoxicity.

Metabotropic glutamate receptor 5-regulated Elk-1 phosphorylation and immediate early gene expression in striatal neurons.

The Galphaq protein-coupled metabotropic glutamate receptor subtype-5 (mGluR5) is densely expressed in medium spiny projection neurons of striatum. Emerging evidence suggests a significant role of mGluR5 in the addictive plasticity of striatal neurons that is likely derived from inducible cellular gene expression related to stimulation of mGluR5 and associative signaling proteins. In this study, we found that activation of mGluR5 with a selective agonist (RS)-2-chloro-5-hydroxy-phenylglycine (CHPG) induced a rapid and transient phosphorylation of a transcription regulator Elk-1 in cultured striatal neurons from rat E19 embryos or neonatal day-1 pups. The Elk-1 phosphorylation was dose-dependent and occurred in neurochemically identified GABAergic neurons, but not glia. A series of experiments further demonstrated that the CHPG-stimulated Elk-1 phosphorylation was mediated through selective activation of mGluR5-regulated phospholipase C and associative second messenger system, i.e. 1,4,5,-triphosphate-sensitive Ca2+ release. Moreover, the Elk-1 phosphorylation was partially dependent on mGluR5-mediated co-activation of NMDA, but not kainate/AMPA receptors and L-type voltage-operated Ca2+ channels. Using an immediate early gene c-fos as a report of inducible gene expression, we found that CHPG induced marked c-fos mRNA expression. The c-fos induction kinetically corresponded to the Elk-1 phosphorylation and was attenuated by antisense oligonucleotides that selectively knocked down Elk-1 proteins. These results indicate that glutamatergic tone on mGluR5 is positively coupled to Elk-1 phosphorylation in striatal neurons via multiple signaling mechanisms involving Ca2+ release and NMDA activation, and the mGluR5-mediated Elk-1 phosphorylation facilitates gene transcription.

Glutamate-regulated Behavior, Transmitter Release, Gene Expression and Addictive Plasticity in the Striatum: Roles of Metabotropic Glutamate Receptors

Metabotropic glutamate receptors (mGluRs) are G-protein-coupled receptors and are densely expressed in medium spiny projection neurons of striatum. Emerging evidence demonstrates a significant role of mGluRs in the regulation of striatal functions. Activation of mGluRs alters local transmitter release and behaviors of experimental animals. In particular, mGluRs regulate phosphorylation of several key signaling proteins (protein kinases and transcription factors) resulting in significant changes in immediate early gene and neuropeptide gene expression in striatal neurons. The prominent involvement of mGluRs in genomic responses to synaptic stimulation is considered to play a pivotal role in the development of synaptic/neuronal plasticity underlying long-term adaptive changes in cellular physiology related to a variety of neurologic disorders. Available data indicate that the eight subtypes of mGluRs have distinct effects on gene expression. The group I subtypes (mGluR1/5) facilitate, whereas group II (mGluR2/3) and III (mGluR4/6/7/8) subtypes inhibit, gene expression. Due to their significance in regulating drug action, mGluRs have been considered as promising targets for the development of novel therapeutic drugs for the treatment of drug addiction. The present review summarizes the roles of mGluRs in the regulation of behavior, transmitter release and particularly genomic responses in striatal neurons to dopamine stimulation, following a description of anatomical organization of mGluRs in the striatum. The possible pre- and postsynaptic mechanisms that process mGluR modulatory effects are also discussed in detail. Finally, potential of mGluRs as targets for the development of therapeutic drugs for addictive and other mental illnesses concludes this review.

Sustained Behavioral Stimulation Following Selective Activation of Group I Metabotropic Glutamate Receptors in Rat Striatum

Group I metabotropic glutamate receptors (mGluRs) are densely expressed in the medium-sized spiny projection neurons of striatum. Activation of this group of the mGluRs modifies neuronal physiology through stimulation of phosphoinositide hydrolysis and intracellular Ca 2+ release. Unlike the ionotropic glutamate receptors that mediate rapid synaptic transmission, activation of the mGluRs produces long-lasting actions brought about by modulation of activities of intracellular effectors. In this study, the role of the group I mGluRs in the modulation of extrapyramidal motor function was examined using a group I selective agonist, 3,5-dihydroxyphenylglycine (DHPG), in chronically cannulated rats. Bilateral injections of DHPG at a series of subtoxic doses (20, 40, 80, and 160 nmol) into the central part of the dorsal striatum produced hyperlocomotion and a unique stereotypical behavior (spontaneous and repetitive twitching movement of the head and forepaws) in a dose-dependent manner. The characteristic twitchy behavior usually commenced 30 min to 1 h, and could last as long as 10 to 12 h, after a single injection of the group I agonist. The behavioral responses to DHPG administration were markedly antagonized by intrastriatal injection of the group I antagonist PHCCC (10 nmol), but not the group II/III antagonist MSOPPE (10 nmol). Intrastriatal administration of 20 nmol dantrolene, an inhibitor of intracellular Ca 2+ mobilization, also prevented DHPG-stimulated motor activities. However, blockade of dopamine D 1 receptors with systemic administration of SCH-23390 (0.1 mg/kg, SC) did not alter the ability of DHPG to provoke behavioral activities. These data indicate that selective activation of the DHPG-sensitive group I mGluRs in the striatum can produce long-lasting stimulation of motor activity. DHPG-induced motor stimulation involves the mobilization of intracellular Ca 2+ stores, but appears to be independent of D 1 dopaminergic transmission.