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ABSTRACT: Motor neurons become hyperexcitable during progression of amyotrophic lateral sclerosis (ALS). This abnormal firing behavior has been explained by changes in their membrane properties, but more recently it has been suggested that changes in premotor circuits may also contribute to this abnormal activity. The specific circuits that may be altered during development of ALS have not been investigated. Here we examined the Renshaw cell recurrent circuit that exerts inhibitory feedback control on motor neuron firing. Using two markers for Renshaw cells (calbindin and cholinergic nicotinic receptor subunit alpha2 [Chrna2]), two general markers for motor neurons (NeuN and vesicular acethylcholine transporter [VAChT]), and two markers for fast motor neurons (Chondrolectin and calcitonin-related polypeptide alpha [Calca]), we analyzed the survival and connectivity of these cells during disease progression in the Sod1(G93A) mouse model. Most calbindin-immunoreactive (IR) Renshaw cells survive to end stage but downregulate postsynaptic Chrna2 in presymptomatic animals. In motor neurons, some markers are downregulated early (NeuN, VAChT, Chondrolectin) and others at end stage (Calca). Early downregulation of presynaptic VAChT and Chrna2 was correlated with disconnection from Renshaw cells as well as major structural abnormalities of motor axon synapses inside the spinal cord. Renshaw cell synapses on motor neurons underwent more complex changes, including transitional sprouting preferentially over remaining NeuN-IR motor neurons. We conclude that the loss of presynaptic motor axon input on Renshaw cells occurs at early stages of ALS and disconnects the recurrent inhibitory circuit, presumably resulting in diminished control of motor neuron firing. © 2012 Wiley Periodicals, Inc.
The Journal of Comparative Neurology 05/2013; 521(7):Spc1. · 3.81 Impact Factor
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Richardson N Leão,
Sanja Mikulovic,
Katarina E Leão,
Hermany Munguba,
Henrik Gezelius, Anders Enjin,
Kalicharan Patra,
Anders Eriksson,
Leslie M Loew,
Adriano B L Tort,
Klas Kullander
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ABSTRACT: The vast diversity of GABAergic interneurons is believed to endow hippocampal microcircuits with the required flexibility for memory encoding and retrieval. However, dissection of the functional roles of defined interneuron types has been hampered by the lack of cell-specific tools. We identified a precise molecular marker for a population of hippocampal GABAergic interneurons known as oriens lacunosum-moleculare (OLM) cells. By combining transgenic mice and optogenetic tools, we found that OLM cells are important for gating the information flow in CA1, facilitating the transmission of intrahippocampal information (from CA3) while reducing the influence of extrahippocampal inputs (from the entorhinal cortex). Furthermore, we found that OLM cells were interconnected by gap junctions, received direct cholinergic inputs from subcortical afferents and accounted for the effect of nicotine on synaptic plasticity of the Schaffer collateral pathway. Our results suggest that acetylcholine acting through OLM cells can control the mnemonic processes executed by the hippocampus.
Nature Neuroscience 10/2012; · 15.53 Impact Factor
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ABSTRACT: Gamma motor neurons (MNs), the efferent component of the fusimotor system, regulate muscle spindle sensitivity. Muscle spindle sensory feedback is required for proprioception that includes sensing the relative position of neighboring body parts and appropriately adjust the employed strength in a movement. The lack of a single and specific genetic marker has long hampered functional and developmental studies of gamma MNs. Here we show that the serotonin receptor 1d (5-ht1d) is specifically expressed by gamma MNs and proprioceptive sensory neurons. Using mice expressing GFP driven by the 5-ht1d promotor, we performed whole-cell patch-clamp recordings of 5-ht1d::GFP⁺ and 5-ht1d::GFP⁻ motor neurons from young mice. Hierarchal clustering analysis revealed that gamma MNs have distinct electrophysiological properties intermediate to fast-like and slow-like alpha MNs. Moreover, mice lacking 5-ht1d displayed lower monosynaptic reflex amplitudes suggesting a reduced response to sensory stimulation in motor neurons. Interestingly, adult 5-ht1d knockout mice also displayed improved coordination skills on a beam-walking task, implying that reduced activation of MNs by Ia afferents during provoked movement tasks could reduce undesired exaggerated muscle output. In summary, we show that 5-ht1d is a novel marker for gamma MNs and that the 5-ht1d receptor is important for the ability of proprioceptive circuits to receive and relay accurate sensory information in developing and mature spinal cord motor circuits.
Molecular and Cellular Neuroscience 01/2012; 49(3):322-32. · 3.66 Impact Factor
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Anders Enjin,
Nadine Rabe,
Stan T Nakanishi,
Anna Vallstedt,
Henrik Gezelius,
Fatima Memic,
Magnus Lind,
Tord Hjalt,
Warren G Tourtellotte,
Carl Bruder,
Gregor Eichele,
Patrick J Whelan,
Klas Kullander
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ABSTRACT: Spinal cholinergic neurons are critical for motor function in both the autonomic and somatic nervous systems and are affected in spinal cord injury and in diseases such as amyotrophic lateral sclerosis (ALS) and spinal muscular atrophy. Using two screening approaches and in situ hybridization, we identified 159 genes expressed in typical cholinergic patterns in the spinal cord. These include two general cholinergic neuron markers, one gene exclusively expressed in motor neurons, and nine genes expressed in unknown subtypes of somatic motor neurons. Further, we present evidence that chondrolectin (Chodl) is expressed by fast motor neurons and that estrogen-related receptor beta (ERRbeta) is a candidate marker for slow motor neurons. In addition, we suggest paired-like homeodomain transcription factor 2 (Pitx2) as a marker for cholinergic partition cells.
The Journal of Comparative Neurology 06/2010; 518(12):2284-304. · 3.81 Impact Factor
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ABSTRACT: Glutamate-induced excitotoxicity has been suggested to influence pathogenesis in amyotrophic lateral sclerosis (ALS). Vesicular glutamate transporters (VGLUTs) are responsible for transport of glutamate into synaptic vesicles. Nerve terminals that envelop motor neurons in the spinal cord contain VGLUT2 and are likely responsible for most glutamate release on motor neurons. The role of VGLUT2 in ALS and its potential role to influence motor neuron survival have not previously been studied. Here, in a mouse model of ALS, we show that genetic reduction of VGLUT2 protein levels rescues motor neurons in the lumbar spinal cord and in the brainstem as well as neuromuscular junctions in tibialis anterior. Although the number of remaining motor neurons increased, neither disease onset nor life span was affected. We also show that the motor neuron subpopulation-specific markers calcitonin/calcitonin-related polypeptide alpha (Calca) and estrogen related receptor beta (ERRbeta) respond in a similar way to reduced VGLUT2 as the whole motor neuron population suggesting that the rescued motor neurons are not of a particular motor unit type. Taken together, this suggests that reduced levels of VGLUT2 decrease motor neuron degeneration but do not prevent loss of motor neuron function in the SOD1(G93A) mouse model for ALS.
Neurobiology of Disease 09/2009; 37(1):58-66. · 5.40 Impact Factor
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Heike Wegmeyer,
Joaquim Egea,
Nadine Rabe,
Henrik Gezelius,
Alessandro Filosa, Anders Enjin,
Frederique Varoqueaux,
Katrin Deininger,
Frank Schnütgen,
Nils Brose,
Rüdiger Klein,
Klas Kullander,
Andrea Betz
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ABSTRACT: Neuronal network formation in the developing nervous system is dependent on the accurate navigation of nerve cell axons and dendrites, which is controlled by attractive and repulsive guidance cues. Ephrins and their cognate Eph receptors mediate many repulsive axonal guidance decisions by intercellular interactions resulting in growth cone collapse and axon retraction of the Eph-presenting neuron. We show that the Rac-specific GTPase-activating protein alpha2-chimaerin binds activated EphA4 and mediates EphA4-triggered axonal growth cone collapse. alpha-Chimaerin mutant mice display a phenotype similar to that of EphA4 mutant mice, including aberrant midline axon guidance and defective spinal cord central pattern generator activity. Our results reveal an alpha-chimaerin-dependent signaling pathway downstream of EphA4, which is essential for axon guidance decisions and neuronal circuit formation in vivo.
Neuron 10/2007; 55(5):756-67. · 14.74 Impact Factor
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ABSTRACT: Glutamatergic excitatory neurotransmission is dependent on glutamate release from presynaptic vesicles loaded by three members of the solute carrier family, Slc17a6-8, which function as vesicular glutamate transporters (VGLUTs). Here, we show that VGLUT2 (Slc17a6) is required for life ex utero. Vglut2 null mutant mice die immediately after birth because of the absence of respiratory behavior. Investigations at embryonic stages revealed that neural circuits in the location of the pre-Bötzinger (PBC) inspiratory rhythm generator failed to become active. However, neurons with bursting pacemaker properties and anatomical integrity of the PBC area were preserved. Vesicles at asymmetric synapses were fewer and malformed in the Vglut2 null mutant hindbrain, probably causing the complete disruption of AMPA/kainate receptor-mediated synaptic activity in mutant PBC cells. The functional deficit results from an inability of PBC neurons to achieve synchronous activation. In contrast to respiratory rhythm generation, the locomotor central pattern generator of Vglut2 null mutant mice displayed normal rhythmic and coordinated activity, suggesting differences in their operating principles. Hence, the present study identifies VGLUT2-mediated signaling as an obligatory component of the developing respiratory rhythm generator.
Journal of Neuroscience 12/2006; 26(47):12294-307. · 7.11 Impact Factor
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ABSTRACT: Central pattern generators (CPGs) are defined as neuronal circuits capable of producing a rhythmic and coordinated output without the influence of sensory input. The locomotor and respiratory neuronal circuits are two of the better-characterized CPGs, although much work remains to fully understand how these networks operate. Glutamatergic neurons are involved in most neuronal circuits of the nervous system and considerable efforts have been made to study glutamate receptors in nervous system signaling using a variety of approaches. Because of the complexity of glutamate-mediated signaling and the variety of receptors triggered by glutamate, it has been difficult to pinpoint the role of glutamatergic neurons in neuronal circuits. In addition, glutamate is an amino acid used by every cell, which has hampered identification of glutamatergic neurons. Glutamatergic excitatory neurotransmission is dependent on the release from glutamate-filled presynaptic vesicles loaded by three members of the solute carrier family, Slc17a6-8, which function as vesicular glutamate transporters (VGLUTs). Recent data describe that Vglut2 (Slc17a6) null mutant mice die immediately after birth due to a complete loss of the stable autonomous respiratory rhythm generated by the pre-Bötzinger complex. Surprisingly, we found that basal rhythmic locomotor activity is not affected in Vglut2 null mutant embryos. With this perspective, we discuss data regarding presence of VGLUT1, VGLUT2 and VGLUT3 positive neuronal populations in the spinal cord.
Journal of Physiology-Paris 100(5-6):297-303. · 1.31 Impact Factor
