Functional and ultrastructural analysis of group I mGluR in striatal fast-spiking interneurons

Striatal parvalbumin-containing fast-spiking (FS) interneurons provide a powerful feedforward GABAergic inhibition on spiny projection neurons, through a widespread arborization and electrical coupling. Modulation of FS interneuron activity might therefore strongly affect striatal output. Metabotropic glutamate receptors (mGluRs) exert a modulatory action at various levels in the striatum. We performed electrophysiological recordings from a rat striatal slice preparation to investigate the effects of group I mGluR activation on both the intrinsic and synaptic properties of FS interneurons. Bath-application of the group I mGluR agonist, (S)-3,5-dihydroxyphenylglycine (3,5-DHPG), caused a dose-dependent depolarizing response. Both (S)-(+)-alpha-amino-4-carboxy-2-methylbenzeneacetic acid (LY367385) and 7-(hydroxyimino)cyclopropa[b]chromen-1a-carboxylate ethyl ester (CPCCOEt), selective mGluR1 antagonists, significantly reduced the amplitude of the membrane depolarization caused by 3,5-DHPG application. Conversely, mGluR5 antagonists, 2-methyl-6-(phenylethylnyl)pyridine hydrochloride (MPEP) and 6-methyl-2-(phenylazo)-3-pyridinol (SIB1757), were unable to affect the response to 3,5-DHPG, suggesting that only mGluR1 contributes to the 3,5-DHPG-mediated excitatory action on FS interneurons. Furthermore, mGluR1 blockade significantly decreased the amplitude of the glutamatergic postsynaptic potentials, whereas the mGluR5 antagonist application produced a small nonsignificant inhibitory effect. Surprisingly, our electron microscopic data demonstrate that the immunoreactivity for both mGluR1a and mGluR5 is expressed extrasynaptically on the plasma membrane of parvalbumin-immunoreactive dendrites of FS interneurons. Together, these results suggest that despite a common pattern of distribution, mGluR1 and mGluR5 exert distinct functions in the modulation of FS interneuron activity.     

匹罗卡品致痫大鼠海马神经肽Y中间神经元数目变化及其轴突出芽

目的:探讨神经肽Y(neuropeptide Y,NPY)中间神经元在颞叶癫痫的发生和自我修复中的作用.方法:建立匹罗卡品致痫模型,应用免疫组织化学技术动态观察大鼠海马NPY中间神经元的数目变化及其轴突出芽.结果:实验组大鼠腹腔注射氯化锂-匹罗卡品后,癫痫持续状态(status epilepticus, SE)诱发成功率为92.9%,死亡率19.2%.免疫组织化学结果显示,实验组大鼠海马门区NPY中间神经元数目在SE后下降,至7 d时降至最低(P<0.01),慢性期开始恢复,SE后60 d时NPY神经元数目与对照组相比仍有减少(P<0.05);CA区域除SE后7 d CA3区NPY神经元数目稍减少外(P<0.05),其余时间点均无明显变化(P>0.05);SE后30 d齿状回分子层可见增多的NPY阳性纤维.结论:NPY中间神经元在不同部位不同时段对颞叶癫痫所致损伤的敏感性不同,NPY中间神经元的缺失在颞叶癫痫发生中起重要作用,NPY中间神经元的轴突出芽在颞叶癫痫的自我修复中起作用.     

Differential induction of long term synaptic plasticity in inhibitory synapses of the hippocampus

Long term synaptic plasticity has been more extensively studied in excitatory synapses, but it is also a property of inhibitory synapses. Many inhibitory synapses target hippocampal pyramidal neurons of the CA1 region. They originate from several interneuron classes that subdivide the surface area that they target on the pyramidal cell. Thus, many interneurons preferentially innervate the perisomatic area and axon hillock of the pyramidal cells while others preferentially target dendritic branches and spines. Methods to preferentially activate dendritic or somatic inhibitory synapses onto pyramidal neurons have been devised. By using these methods, the present work demonstrates that a stimulation pattern that induces long term potentiation (LTP) in excitatory synapses of the Schaffer collaterals is also capable of inducing distinct types of long term plastic changes in different classes of inhibitory synapses: Induction of long term depression (LTD) was seen in dendritic inhibitory synapses whereas LTP was observed in somatic inhibitory synapses. These findings suggest that inhibitory synapses arising from different interneuron classes may respond to the same stimulus according to their specific plastic potential enabling a spatial combinatorial pattern of inhibitory effects onto the pyramidal cell.     

Exercise protects from hippocampal inflammation and neurodegeneration in experimental autoimmune encephalomyelitis

Exercise is increasingly recommended as a supportive therapy for people with Multiple Sclerosis (pwMS). While clinical research has still not disclosed the real benefits of exercise on MS disease, animal studies suggest a substantial beneficial effect on motor disability and pathological hallmarks such as central and peripheral dysregulated immune response. The hippocampus, a core area for memory formation and learning, is a brain region involved in MS pathophysiology. Human and rodent studies suggest that the hippocampus is highly sensitive to the effects of exercise, the impact of which on MS hippocampal damage is still elusive.Here we addressed the effects of chronic voluntary exercise on hippocampal function and damage in experimental autoimmune encephalomyelitis (EAE), animal model of MS. Mice were housed in standard or wheel-equipped cages starting from the day of immunization and throughout the disease course. Although running activity was reduced during the symptomatic phase, exercise significantly ameliorated motor disability. Exercise improved cognition that was assessed through the novel object recognition test and the nest building in presymptomatic and acute stages of the disease, respectively. In the acute phase exercise was shown to prevent EAE-induced synaptic plasticity abnormalities in the CA1 area, by promoting the survival of parvalbumin-positive (PV+) interneurons and by attenuating inflammation. Indeed, exercise significantly reduced microgliosis in the CA1 area, the expression of tumour necrosis factor (TNF) in microglia and, to a lesser extent, the hippocampal level of interleukin 1 beta (IL-1β), previously shown to contribute to aberrant synaptic plasticity in the EAE hippocampus. Notably, exercise exerted a precocious and long-lasting mitigating effect on microgliosis that preceded its neuroprotective action, likely underlying the improved cognitive function observed in both presymptomatic and acute phase EAE mice.Overall, these data provide evidence that regular exercise improves cognitive function and synaptic and neuronal pathology that typically affect EAE/MS brains.     

A morphological investigation of thalamic neurons by intracellular HRP staining in cats

Morphological analysis of 77 neurons in the ventroanterior (VA), ventrolateral (VL), ventromedial (VM), and central lateral (CL) nuclei was performed by intracellular HRP staining in combination with electrophysiological studies. The neurons were classified into four groups according to either electrophysiological or morphological criteria, i.e., 20 relay neurons (18 thalamocortical (T-C) and two thalamocaudate (T-Cd) relay neurons), 17 projection neurons, 36 unidentified neurons, and four presumed interneurons. All 36 unidentified neurons had morphological features similar to those of relay and projection neurons. All neurons except four presumed interneurons had dendrites sparsely covered with spinelike appendages. Most of their dendrites displayed a spherically radiating branching pattern, and a few showed a tufted or linearly oriented pattern. Sizes of somata and dendritic radii were compared in entopeduncular (Ent)-responsive (n = 25) and cerebellar (CN)-responsive groups (n = 37) in VA, VL, and VM nuclei. The soma size was similar in VL (18-21 X 29-34 micron) and VM (15-19 X 29-31 micron), but in VA, CN-responsive neurons (15 X 30 micron) seemed to be smaller than Ent-responsive ones (22 X 36 micron). The largest dendritic field of neurons in each thalamic nucleus was similar in both groups. They were about 250-320 micron in radius. Diameters of axons were also compared but no statistically significant difference was detected (i.e., 1.5 +/- 0.3 (mean +/- S.D.) micron for the Ent group and 1.7 +/- 0.5 micron for the CN group). Three types of axonal trajectories were noted, i.e., neurons projecting their axons dorsolaterally, ventrolaterally, or horizontally. Fourteen neurons out of 37 relay and projection neurons gave off several fine distal axon collaterals in the thalamic reticular nucleus, and one T-Cd, three projection, and one unidentified neurons gave off proximal axon collaterals near the soma-dendritic domain in addition to those in the thalamic reticular nucleus. Four neurons classified as presumed interneurons had smaller somata (9-13 X 18-23 micron) and varicose dendrites. Three of them received Ent-induced inhibitory postsynaptic potentials (IPSPs) or CN-induced excitatory postsynaptic potentials (EPSPs). Several presumed axon terminals were found to cover the soma of an adjacent neuron, which seemed to indicate their inhibitory nature. The proximal axon collaterals in the ventral thalamic nuclei may consist of local inhibitory circuits with presumed interneurons in addition to other inhibitory circuits with thalamic reticular neurons.     

Immunocytochemical heterogeneity of somatostatin‐expressing GABAergic interneurons in layers II and III of the mouse cingulate cortex: A combined immunofluorescence/design‐based stereologic study

Many neurological diseases including major depression and schizophrenia manifest as dysfunction of the GABAergic system within the cingulate cortex. However, relatively little is known about the properties of GABAergic interneurons in the cingulate cortex. Therefore, we investigated the neurochemical properties of GABAergic interneurons in the cingulate cortex of FVB‐Tg(GadGFP)45704Swn/J mice expressing green fluorescent protein (GFP) in a subset of GABAergic interneurons (GFP‐expressing inhibitory interneurons [GINs]) by means of immunocytochemical and design‐based stereologic techniques. We found that GINs represent around 12% of all GABAergic interneurons in the cingulate cortex. In contrast to other neocortical areas, GINs were only found in cortical layers II and III. More than 98% of GINs coexpressed the neuropeptide somatostatin (SOM), but only 50% of all SOM + neurons were GINs. By analyzing the expression of calretinin (CR), calbindin (CB), parvalbumin, and various neuropeptides, we identified several distinct GIN subgroups. In particular, we observed coexpression of SOM with CR and CB. In addition, we found neuropeptide Y expression almost exclusively in those GINs that coexpressed SOM and CR. Thus, with respect to the expression of calcium‐binding proteins and neuropeptides, GINs are surprisingly heterogeneous in the mouse cingulate cortex, and the minority of GINs express only one marker protein or peptide. Furthermore, our observation of overlap between the SOM + and CR + interneuron population was in contrast to earlier findings of non‐overlapping SOM + and CR + interneuron populations in the human cortex. This might indicate that findings in mouse models of neuropsychiatric diseases may not be directly transferred to human patients. J. Comp. Neurol. 524:2281–2299, 2016. © 2015 Wiley Periodicals, Inc.     

Cholinergic responses in GABAergic and non-GABAergic neurons in the intermediate gray layer of mouse superior colliculus

Neurons in the intermediate gray layer (SGI) of the mammalian superior colliculus (SC) receive dense cholinergic innervations from the brainstem parabrachial region. Such cholinergic inputs may influence execution of orienting behaviors. To obtain deeper insights into how the cholinergic inputs modulate the SC local circuits, we analysed the cholinergic responses in identified γ‐aminobutyric acid (GABA)ergic and non‐GABAergic neurons using SC slices obtained from GAD67‐GFP knock‐in mice. The responses of SGI neurons to cholinergic agonists were various combinations of fast inward currents mediated mainly via α4β2 and partly by α7 nicotinic receptors (nIN), slow inward currents caused by activation of M1 plus M3 muscarinic receptors (mIN), and slow outward currents caused by activation of M2 muscarinic receptors (mOUT). The most common cholinergic responses in non‐GABAergic neurons was nIN + mIN + mOUT (38/68), followed by nIN + mIN (16/68), nIN + mOUT (11/68), nIN only (2/68), and no response (1/68). On the other hand, the major response pattern in GABAergic neurons was either nIN only (26/54) or nIN + mIN (21/54), followed by nIN + mOUT (4/54), mOUT only (2/54), and no response (1/54). Thus, major effects of cholinergic inputs to both SGI GABAergic and non‐GABAergic neurons are excitatory, but the response patterns in these two types of SGI neurons are different. Thus, actions of the cholinergic inputs to non‐GABAergic and GABAergic SGI neurons are not simple push–pull mechanisms, like excitation vs inhibition, but might cooperate to balance the level of excitation and inhibition for setting the state of the response property of the local circuit.     

The dynamics of analogue signalling in local networks controlling limb movement

Communication by analogue signals is relatively common in arthropod local networks. In the locust, non‐spiking local interneurons play a key role in controlling sets of motor neurons in the generation of local reflex movements of the limbs. Here, our aim was two‐fold. Our first aim was to determine the coding properties of a subpopulation of these interneurons by using system identification approaches. To this end, the femoro‐tibial chordotonal organ, which monitors the movements of the tibia about the femur, was stimulated with Gaussian white noise and with more natural stimuli corresponding to the movements of the tibia during walking. The results showed that the sample of interneurons analysed displayed a wide, and overlapping, range of response characteristics. The second aim was to develop and test improved data analysis methods for describing neuronal function that are more robust and allow statistical analysis, a need emphasized by the high levels of background neuronal activity usually observed. We found that nonlinear models provided an improved fit in describing the response properties of interneurons that were then classified with statistical clustering methods. We identified four distinct categories of interneuron response that can be further divided into nine groups, with most interneurons being excited during extension movements of the leg, reflecting the outputs of upstream spiking local interneurons.