Rebound from Inhibition: Self-Correction against Neurodegeneratio
Journal of Clinical and Cellular Immunology

Journal of Clinical and Cellular Immunology
Open Access

ISSN: 2155-9899

Review Article - (2017) Volume 8, Issue 2

Rebound from Inhibition: Self-Correction against Neurodegeneration?

Shobhana Sivaramakrishnan1* and William P. Lynch2*
1Department of Otolaryngology, Sensory Neuroscience Research Center, West Virginia University School of Medicine, Morgantown, WV 26506, USA
2Department of Integrative Medical Sciences, Northeast Ohio Medical University, Rootstown, OH 44272, USA
*Corresponding Author(s): Shobhana Sivaramakrishnan, Biomedical Research Center, Department of Otolaryngology, West Virginia University School of Medicine, Morgantown, WV 26506, USA, Tel: 304-293-2457 Email:
William P. Lynch, Department of Integrative Medical Sciences, Northeast Ohio Medical University, Rootstown, OH 44272, USA, Tel: 330-325-6137 Email:


Neural networks play a critical role in establishing constraints on excitability in the central nervous system. Several recent studies have suggested that network dysfunction in the brain and spinal cord are compromised following insult by a neurodegenerative trigger and might precede eventual neuronal loss and neurological impairment. Early intervention of network excitability and plasticity might therefore be critical in resetting hyperexcitability and preventing later neuronal damage. Here, the behavior of neurons that generate burst firing upon recovery from inhibitory input or intrinsic membrane hyperpolarization (rebound neurons) is examined in the context of neural networks that underlie rhythmic activity observed in areas of the brain and spinal cord that are vulnerable to neurodegeneration. In a non-inflammatory rodent model of spongiform neurodegenerative disease triggered by retrovirus infection of glia, rebound neurons are particularly vulnerable to neurodegeneration, likely due to an inherently low calcium buffering capacity. The dysfunction of rebound neurons translates into a dysfunction of rhythmic neural circuits, compromising normal neurological function and leading to eventual morbidity. Understanding how virus infection of glia can mediate dysfunction of rebound neurons, induce hyperexcitability and loss of rhythmic function, pathologic features observed in neurodegenerative disorders ranging from epilepsy to motor neuron disease, might therefore suggest a common pathway for early therapeutic intervention.

Keywords: Post-inhibitory rebound firing; Rhythmic neural networks; Calcium buffering; Calcium channels; Motor neuron degeneration; Microglia; NG2 glia; Astrocytes


In human and animal neurodegenerative diseases, neurons undergo functional alterations that lead to cell death and eventual morbidity. Despite widespread CNS occurrence of etiologic triggers, such as abnormal, foreign or misfolded proteins, degenerative mechanisms often select for certain neuronal populations over others. Defining the nature of neuronal vulnerability to the trigger has focused primarily on understanding interactions between the pathogenic proteins and neuronal targets such as cell surface receptors, neurotransmitter transporters, intracellular signal transduction cascades, epigenetic gene regulatory elements, neuron selective endoplasmic reticulum protein folding and degradation pathway components, calcium homeostasis, and/or the activity and kinetics of voltage-gated currents [1-4]. Impaired neurological function can also arise through dysfunction in neural networks, which, by contrast, is not necessarily associated with neuronal loss. Aberrant neuronal activity, which can result from misfolded proteins found, for example, in Alzheimer’s disease, Parkinson’s disease and amyotrophic lateral sclerosis (ALS), and alter signaling pathways, are suggested to lead to network dysfunction and eventual neurological failure [5,6]. Given the complex interplay between direct, indirect, inflammatory and non-inflammatory mechanisms, sorting out elements critical in initiating damage in specific neuron types or unique circuitry, and determining when they come into play, constitutes a challenging task.

One approach towards understanding the bases for neuron-selective pathogenesis is to consider neurodegenerative systems where the identification of etiologic triggers is not confounded by inflammatory/ neuroinflammatory components. In mice, one such neurodegenerative disease is caused by the murine retrovirus, CasBrE, first described by Gardner et al. [7,8].

Because this virus is transmitted from infected dams to newborn offspring through mammary secretions, immune-naïve pups fail to recognize it as foreign and fail to develop an active immune response. Upon entry into the host, CasBrE infects blood-forming tissues, leading to the high serum virus levels necessary to facilitate entry into the CNS before endothelial restriction prevents CNS infection [9,10].

In the CasBrE disease paradigm, retrovirus-induced neurodegeneration targets pre-motor and motor areas as well as auditory and vestibular nuclei [11,12]. Overt clinical manifestations include tremor, spasticity, stilted gate, altered posture, progressive paralysis and ultimately death, a picture analogous to ALS in humans [13-15]. In addition, auditory deficits, which include raised hearing thresholds [16], suggest a loss of synchronous network activity in brainstem circuits. We therefore used the CasBrE model to examine the susceptibility of different neuronal types and networks to degeneration. Our model system was the inferior colliculus, a midbrain nucleus in the central auditory pathway. Cell types in the inferior colliculus can be differentiated by their intrinsic firing patterns [17,18] and local microcircuits are activated by input from the lower brainstem as well as by intrinsic connections between collicular neurons [19-22], providing a system in which to determine why particular neuronal populations succumb to neurodegenerative triggers.

Our results demonstrate that a combination of two factors, the intrinsic firing pattern of a neuron and its incorporation into a specific microcircuit, can be critical in determining vulnerability to degeneration. Neurons that respond to the cessation of an inhibitory input by generating bursts of spikes (referred to as rebound neurons) are particularly susceptible to dysfunction and loss.

Following systemic infection with the virus, rebound firing is abolished and neurons exhibit prolonged spontaneous hyperexcitability that is not tied to inhibition. In addition, the loss of rebound firing in individual neurons propagates into the local network and causes widespread failure of rhythmic activity in the colliculus. In this system, viral infection is restricted to glia and is not observed in neurons, suggesting that the etiologic triggers for failure of the rhythmic neural network, and for progressive neurodegeneration, are glial signals that regulate the ability of neurons to rebound from inhibition [16].

Loss of rhythmic network activity during neurodegeneration

Rhythmic neural circuits are present in many areas of the brain and spinal cord concerned with sensory and motor coordination [22-30]. Circuit activity is maintained by an oscillating excitatory-inhibitory network that can include rebound neurons, which reset excitation in a periodic manner. When rebound neurons receive an inhibitory input, they respond with a burst of spikes that acts as the signal for network activity. Rebound neurons that release the neurotransmitter GABA convey a strong inhibitory signal during the rebound burst period to the connected neurons in the network [31-36]. The signal conveyed by rebound from inhibition therefore acts as a switch to stop or reset excitation in the network. Rebound neurons that release inhibitory neurotransmitters are themselves intrinsically oscillating [37,38], thus, as individual neurons, they have the capacity to set phase transitions between excitation and inhibition. An added benefit of this excitatory-inhibitory oscillation is the limiting of activity to the restricted locus of neurons that form the feedback connections of the network [39].

The loss of rebound firing in a neurodegenerative milieu translates into a breakdown of rhythmic circuits, and an inability to reset the excitatory state of the network, resulting in a prolonged hyperexcitable state. Indeed, in several rodent models of neurodegeneration, hyperexcitability of single neurons co-exists with a loss of rhythmic activity. For example, in the mutant superoxide dismutase (SOD1) rodent model of motor neuron degeneration and ALS, motor neurons in the spinal cord become persistently hyperexcitable. In addition, these mice show deficits in rhythmic behavior that normally originates in rebound firing [40,41] and which manifests as abnormal ventral root rhythms that correlate with disease pathology [42,43]. Neurodegeneration is also associated with altered network activity in brain regions that regulate sleep (basal forebrain, hippocampus) [44] and breathing [45], both of which involve rhythmic circuits. In our model of retrovirus infection, a primary readout of neuronal synchrony, the auditory brainstem response, is severely attenuated and delayed in the inferior colliculus [16]. Taken together, these several studies suggest that a loss of rhythmic behavior coincides with the neurodegenerative state.

The calcium-rebound connection and its failure in neurodegeneration

In normal conditions, the rhythmic cycle is maintained when rebound firing is temporally locked to the preceding inhibition or membrane hyperpolarization [17,22]. Inhibition and the subsequent rebound firing form a temporal gate, during which spike rates are elevated compared to that before the inhibitory input [46,47]. Two critical characteristics of the inhibition-rebound window give the rhythmic network the capacity to adjust its level of excitation to the level of inhibition. First, the amplitude of preceding inhibition determines both the latency and duration of rebound firing. With increasing inhibition, rebound latency decreases, while rebound firing becomes prolonged [17]. Loss or down-regulation of inhibitory input can therefore result in loss or delay of rebound firing. In our retrovirus model of degeneration, rebound neurons in the inferior colliculus lose rebound firing despite normal levels of inhibitory input or intrinsic hyperpolarization [16]. Rebound loss therefore results from the second determinant of the temporal nature of the inhibition-rebound window, namely changes in the behavior of intrinsic ion channels. These changes are discussed below.

Intrinsic ion channels affected by the retrovirus appear to be voltage-gated L-type calcium channels that are activated during rebound from inhibition. When the internal concentration of free calcium is decreased by dialyzing cells with the calcium buffer EGTA, rebound firing is restored. In control mice, in contrast, decreasing internal free calcium abolishes rebound firing [16]. A comparison of the effects of EGTA on the rebound window between infected and uninfected mice reveals that the generation of rebound firing requires an interaction between L- type channels (IL) and the lower-threshold T-type calcium channel (IT), also present in rebound neurons. Calcium influx through IT is unaffected in infected mice, whereas calcium influx through IL is absent. The restoration of rebound firing by EGTA in infected mice indicates no permanent loss of IL subunits. Instead IL is blocked due to a calcium-dependent inactivation of these channels from the cytoplasmic side of the cell membrane. IL thus provides the regenerative current needed to drive rebound firing, and its inactivation in infected mice suggests raised internal calcium levels. Since IT is not subject to calcium-dependent inactivation [48], it is unaffected by increases in the internal calcium concentration. However, since the initial influx of calcium into rebound neurons occurs through IT, the subsequent block of IL suggests that IT must provide the regenerative drive to activate IL from the cytoplasmic side of the membrane. The requirement for calcium entry through both IT and IL during the rebound window, which has been demonstrated in other studies [49,50], and the block of IL, but not IT, following viral infection in the inferior colliculus, indicates that neurodegenerative triggers act at the site of interaction between IT and IL. Firing properties of other neuronal types in the inferior colliculus are unaffected by EGTA dialysis, suggesting that rebound cells must be less capable than other cell types of handling high calcium loads. EGTA dialysis, and the application of nimodipine, an antagonist of IL, also blocks hyperexcitability in rebound neurons, providing strong support for the hypothesis that calcium buffering in rebound neurons is compromised [16]. The retrovirus model of degeneration therefore demonstrates that the vulnerability of rebound neurons arises from a calcium buffering capacity that is normally lower than that of other neuronal cell types in the inferior colliculus.

The importance of calcium buffering in neurodegenerative disorders is well established [51]. In ALS mouse models, for example, motor neurons with low levels of endogenous calcium buffers display enhanced susceptibility to degeneration [52]. The type of endogenous calcium-binding protein as well as the presence of more than one calcium-binding protein in a cell might also be important in resisting degeneration. In this regard, a recent comparison between ALSresistant ocular motor neurons and vulnerable hypoglossal and spinal motor neurons showed that parvalbumin levels correlated with resistance levels [53]. The presence of multiple calcium-binding proteins within neurons might also confer resistance to degeneration. For example, neurons in regions of the inferior colliculus that are resistant to virus-induced degeneration appear to contain both calbindin and calretinin, whereas collicular neurons vulnerable to degeneration contain only parvalbumin [54,55]. Neurons in the deep cerebellar nucleus, which undergo virus-induced degeneration [12] also contain parvalbumin [56], while resistant cerebellar cortex neurons [11] contain parvalbumin, calbindin and calretinin [57]. Calretinin- and calbindin-deficient cerebellar granule cells display rapid spiking and fast neuronal oscillations, alterations of normal rhythmic states and ataxia, which are reduced by increasing calcium-buffering through added cytoplasmic calcium chelators [58,59], suggesting a direct role for calcium-binding proteins in altered rhythmic activity, hyperexcitability and motor coordination.

Does glial-neuronal miscommunication underlie the loss of rhythmic networks?

The retrovirus-induced degenerative model is particularly interesting from the perspective of how glial-neuronal communication may initiate neurodegeneration. Although degenerating neurons appear to be permissive for virus entry events [60], they are not permissive for virus replication or gene expression because the reverse transcribed genome cannot integrate into the chromosomal DNA of non-dividing cells. Moreover, chimeric brain reconstitution experiments demonstrated that early virus replication events are insufficient to precipitate neurodegeneration but rather require expression of the viral ENV protein within host glia to cause disease [61,62]. CNS infection is most prominent in microglia and NG2 glia [11,60,63], however, infection of these two cell populations alone does not appear to be sufficient to cause disease [60]. A third glial cell type, most likely astrocytes, appears to be required for neurodegeneration, but its identity remains in question since virus expression in this cell type appears to be down-regulated upon their differentiation from glial progenitor cells [64,65]. Interestingly, infection of glial progenitor cells with either neurovirulent of non-neurovirulent ectopic viruses inhibits their differentiation into mature oligodendrocytes, however, the neurovirulent virus appears to bias differentiation towards an astrocytic fate, whereas the isogenic non-neurovirulent virus appears to suspend cells in a progenitor-like state [64]. How this alteration of glial differentiation may affect neuronal excitability and circuit behavior remains unexplored.

Importantly, direct infection by CasBrE or related neurovirulent viruses is not directly cytotoxic to any glia or their progenitors, however, NG2 cells (aka, oligodendrocyte progenitor cells; OPCs) appear to be particularly vulnerable to the excitotoxic milieu of dysregulated circuits and hyperactive neurons [64,66]. NG2/OPCinduced cell damage is characterized by effacement of the cytoplasm, while largely sparing nuclear structures. This secondary “spongiform” pattern follows initial post-synaptic vacuolation associated with the dendrites of susceptible neurons [11,16,67,68]. It is now well-established that both excitatory and inhibitory neurons make synaptic contact with NG2 glia, and that these cells possess a variety of neurotransmitter receptors and ion channels [69]. Although these cells have been observed to exhibit action potentials, regenerative events are infrequent and thus, arguably inconsequential [69,70].

It is presently unclear how a non-functional NG2-neuron connection could lead to hyperexcitability and loss of rhythmic networks. An attractive hypothesis might stem from the primary characteristic of NG2 cells, namely their polyfunctionality [71]. Because NG2 cells can differentiate into oligodendrocytes, astrocytes and, in some cases, neurons, and they connect synaptically to neurons [72], virus-induced dormancy could result in large-scale dysregulation of external calcium levels, with consequences for resting calcium levels in both glia and neurons, regulated by calcium leak channels. It has been shown that buffering calcium concentrations within astrocytes prevents neurons from generating rhythms; and rhythmic activity is restored by adding astrocytic calcium-binding proteins to the extracellular space [73]. Whether NG2 cells participate in direct ionic buffering remains to be determined, but their ion channel/transporter expression profile suggests it is possible [69]. Alternatively, NG2 infection could act indirectly to affect astrocyte density, since CasBrE appears to bias glial differentiation towards astrocytes [64]. Whether differentiating astrocytes effectively buffer extracellular calcium in CasBrE-induced disease has not been addressed, since infection of these cells is not readily observable in the CasBrE model [11,60,65]. Nonetheless, this scenario is reminiscent of HIV CNS infection, where astrocyte infection is infrequent and non-productive, but nevertheless appears to be responsible for disruption of the blood brain barrier and death of certain gap junction-connected cells [74,75].

Regardless of whether the etiologic mechanism involves NG2 glia or astrocytes, a non-functional glial-neuronal connection might act in two ways to further degeneration. First, it might serve as a critical point of failure to regulate resting neuronal calcium levels, and second, it might be the factor that is responsible for the neuron selective aspect of neurodegeneration, namely that neurons with a low calcium buffering capacity, such as rebound neurons, are targeted for degeneration (Figure 1). An example of glia as a critical point may be represented by recent findings on perisynaptic schwann cells (PSCs), glial cells present at the neuromuscular junction (NMJ). PSCs decode motor neuron firing to muscles that can be translated into their detection of synaptic damage. Through synaptically-evoked PSC calcium transients, PSCs can shift to an activated state that initiates synapse-repairing processes. Examination of this feature of PSCs in the G37R mutant SOD1 transgenic ALS mouse model suggests that PSCs abnormally decode hyperexcitability at the neuromuscular junction, fail to transition into their reparative state, and thus contribute to NMJ denervation [76]. Since NG2 cells also integrate global and dendritic calcium signals and display calcium transients in response to neural activity [77], it suggests that similar mechanisms may be operating at rebound neuron synapses during rhythmic circuit disruption. Interestingly, deletion of NG2 cells in the CNS has no obvious neuropathologic sequelae per se [78], however, a detailed examination of associated neuronal activities has yet to be examined under conditions where they have been knocked out globally, so it may be premature to speculate on whether their presence is critical for normal circuit function. Thus, the function of NG2 cells in the CNS, beyond their ability to act as glial precursors, remains enigmatic.


Figure 1: Model of glial-mediated loss of rhythmic activity following retroviral infection. Excitatory input (red spikes, red neuron) to a circuit consisting of recurrently connected rebound neurons (blue neurons) results in an output of periodic oscillating bursts (violet output neuron, violet spikes). Both rebound neurons are inhibitory, forming a recurrent inhibitory circuit that converts a sustained excitatory input to a bursting pattern due to the alternation between inhibition and rebound firing. A) In the uninfected condition, increases in calcium concentrations in the extracellular space, which result from activity in the rebound network, are sequestered by surrounding glia. Glial activation required to begin the process of calcium-sequestration is initiated by NG2 cells through their synaptic connections to rebound neurons, their ability to transduce signals through action potential generation, and their connections to other glial cells. As a result, there is minimal calcium entry into rebound neurons through neuronal calcium leak channels. L-type Ca++ channels underlying rebound spiking recover rapidly from calcium-dependent inactivation and the rebound-initiated rhythm is maintained during constant excitatory input. The consequent alternation between inhibition and rebound spiking that result in rhythmic bursting in the output neuron also serves to prevent activation of excitatory conductances in the output neuron that could evoke arrhythmic firing. B) Following infection and subsequent loss of NG2 function, an excitatory input to the rebound network may evoke an initial rebound response (not illustrated). However, calcium concentrations build up in the extracellular space, as a result of which, calcium enters rebound neurons through calcium leak channels. Increased cytoplasmic calcium leads to prolonged inactivation of L-type Ca++ channels, with subsequent failure to generate rebound spiking following inhibition. Inhibition within the rebound network is therefore no longer able to convert a sustained excitatory input to a rhythmic output. Consequently, the output neuron responds to the sustained excitation both as a follower neuron and with added intrinsic conductances that prolong firing and can result in hyperexcitability. At early times following glial disruption and subsequent accumulation of calcium ions in the extracellular space, rhythm-generation remains but is abnormal (Output: early). As the accumulation of extracellular calcium increases, calcium entering rebound neurons through calcium leak channels is unable to be buffered sufficiently. Rebound neurons become hyperexcitable and their inhibitory effect on the output neuron is transiently elevated, resulting in loss of spiking and arrhythmic firing (Output: late). The loss of rebound neurons in the network at later times results in the absence of their inhibitory modulation, and the output becomes non-rhythmic and prolonged (Output: very late).

Despite the parallel occurrence of glial infection and neuronal vacuolation, a functional glial-neuronal link in retrovirus-induced degeneration is currently tenuous. In the inferior colliculus, for example, infected microglia and NG2 cells are observed in close proximity to degenerating neurons [11,16,60,64]. Their infection rates increase alongside the increased loss of rebound activity, suggesting that glial-neuron connections might be critical to disease or its progression. A disconcerting finding in this model is that infected microglia are immunologically and reactively blind to infection by CasBrE, both in vitro and in vivo [11,60,62,79,80]. Similarly, astrocytes are not activated by CNS virus infection [11], but astrogliosis can arise later in the pathogenic process if the disease kinetics are slowed [12]. These findings imply that microglial and astrocytic neuroinflammation arises as a response to neuronal damage rather than a causative factor in disruption of rebound firing or rhythmic circuits. However, because glial infection rates are high following the systemic administration of retrovirus [11,16,66,81], normal glial regulation of neuronal activity, which involves glial vesicle trafficking, ionic gradients and calcium levels [82], particularly in the extracellular space surrounding neurons, might be compromised. Consequently, associated glial pathways, such as downstream activation of NG2 cells by microglia [83] could become nonfunctional if infected microglia become insensitive to neuronal signaling. It has been demonstrated that CNS damage signals readily activate infected microglia in vivo, which in turn inhibits CasBrE induced neurodegeneration [84], a finding that is consistent with the idea that infected microglial cells remain functional but not activated [80]. Thus, it is likely that microglia fail to recognize hyperactive rebound neurons and/or rhythmic circuit alterations per se , but do respond once overt cell damage arises. Whether they contribute to this dysregulation is a more challenging question, especially when considered in the context of neurovirulent amphotropic retrovirus CNS infection, where NG2 cells and microglia are together insufficient to precipitate neurodegenerative changes [60]. If select intercellular signaling functions of microglia (reviewed in [85]) are compromised, like their ability to signal to astrocytes via ATP release [86,87], and/or signal to NG2 glia by transforming growth factor beta-1 [83], and this alteration is combined with altered NG2 glia and astrocyte functions, it might create a situation where neuronal and circuit functions are inappropriately modulated. Thus, retroviral infection might trigger large-scale degeneration of neurons through the disruption of an intrinsic inter-dependence of glial cell communication.

Concluding Remarks

Computational models suggest that the recruitment of a certain criterion number of neurons is necessary to initiate and maintain rhythms. If neuronal recruitment in the rhythmic circuit drops below 1 neuron/ms, the network is no longer able to generate spontaneous rhythms [88]. This suggests that neuronal loss is not required for network dysfunction; instead a slowing down of the network is sufficient to prevent feedback rhythmic behavior. Of particular note is work showing that the use of a treadmill to re-establish push-pull modulation between excitatory and inhibitory inputs during locomotor rhythmic activity [89], when combined with stem cell transplantation, improves recovery by supplying the inhibitory component of the locomotor rhythm [90]. Thus, despite the presence of neurodegenerative triggers, inhibitory plasticity in neural networks may be important in the restoration or recovery of neurological function. Rhythmic connections in the central nervous system cross long distances. For example, the output of pacemaker neurons in the cerebellum [91] is translated into oscillations of the same frequency in the thalamus through long-distance propagation of oscillating excitatory activity [92]. Alterations in local rhythmic networks are therefore likely to affect distant brain regions. Enhancing network plasticity might prevent propagation of abnormal rhythms from local neuronal populations to large scale networks.

Our studies in the retroviral model indicate that neurological impairments resulting from neurodegenerative triggers may be caused by dysfunctional neuron-glia interactions rather than neuronal loss in rhythmic networks. Simple C-type gamma retroviruses, like CasBrE, require nuclear membrane breakdown for viral integration, and thus in the postnatal CNS, viral infection is restricted to dividing glia and neuronal progenitors that persist in the cerebellar cortex, the hippocampal dentate gyrus, and olfactory bulbs [11,65]. Interestingly, neurons that do become infected by CasBrE do not degenerate despite expressing high levels of viral protein, although it has yet to be examined if infection alters their neurophysiological properties.

We speculate that the degenerative cascade may be initiated by a failing NG2-neuron connection. NG2 cells become altered and die in response to CasBrE-altered regulation of neuronal excitability rather than due to direct infection [64,66]. It is of interest that this cellular damage is not recognized as a damage associated molecular pattern (DAMP) signal by the innate immune system to activate a broad neuroinflammatory response as suggested by others [93]. Perhaps in the context of a different (mouse) genetic background [94,95], or if this cascade were initiated under conditions where immune system development and antigen tolerance was not operating, these changes could constitute an inflammatory initiator, such as has been speculated about viral triggers of multiple sclerosis (MS) [96]. Several recent lines of evidence have implicated human endogenous retrovirus (HERV) expression in MS etiology [97]. This includes findings showing viral protein and particle expression in association with blood and MS brain lesions [96], genetic linkage analyses showing MS association with several HERV loci [98-101], HERV Env viral transduction mouse models showing neuroinflammatory pathology similar to MS [97], and studies showing how HERV-W Env/Syncitin expression in astrocytes is toxic to oligodendrocytes [97,102]. Similarly, HERV-K expression has been implicated in sporadic ALS [103], and HERV-K Env transgenic mice show an ALS-like motor neuron disease phenotype [104]. The parallels in these systems raise the possibility that disruption of selective rhythmic neural circuits could underpin a variety of inflammatory and non-inflammatory neurodegenerative diseases, and highlight the utility of investigating circuit properties and their unique neuronal make-up and their modulation by associated glial components.


Supported by grants NIH R01 DC008120, NIH R01 NS37614, ARRA Supplement DC008120-05S1, State of Ohio Research Incentive grant.

Conflict of Interest

The authors declare no competing financial interests.


  1. Nedergaard M, Rodríguez JJ, Verkhratsky A (2010) Glial calcium and diseases of the nervous system.  Cell Calcium 47: 140-149.
  2. Boillée S, Vande Velde C, Cleveland DW (2006) ALS: a disease of motor neurons and their nonneuronal neighbors.  Neuron 52: 39-59.
  3. Berridge MJ (2011) Calcium signalling and Alzheimer's disease.  Neurochem Res 36: 1149-1156.
  4. Appel SH, Smith RG, Alexianu M, Engelhardt J, Mosier D, et al. (1994) Neurodegenerative disease: autoimmunity involving calcium channels.  Ann N Y Acad Sci 747: 183-194.
  5. Saxena S, Caroni P (2011) Selective neuronal vulnerability in neurodegenerative diseases: from stressor thresholds to degeneration. Neuron 71: 35-48.
  6. Palop JJ, Chin J, Mucke L (2006) A network dysfunction perspective on neurodegenerative diseases.  Nature 443: 768-773.
  7. Gardner MB, Henderson BE, Officer JE, Rongey RW, Parker JC, et al. (1973) A spontaneous lower motor neuron disease apparently caused by indigenous type-C RNA virus in wild mice. J Natl Cancer Inst 51: 1243-1254.
  8. Andrews JM, Gardner MB, Wolfgram FJ, Ellison GW, Porter DD, et al. (1974) Studies on a murine form of spontaneous lower motor neuron degeneration--the wobbler (wa) mouse. Am J Pathol 76: 63-78.
  9. Czub M, McAtee FJ, Portis JL (1992) Murine retrovirus-induced spongiform encephalomyelopathy: host and viral factors which determine the length of the incubation period. J Virol 66: 3298-3305.
  10. Czub M, Czub S, McAtee FJ, Portis JL (1991) Age-dependent resistance to murine retrovirus-induced spongiform neurodegeneration results from central nervous system-specific restriction of virus replication. J Virol  65: 2539-2544.
  11. Lynch WP, Czub S, McAtee FJ, Hayes SF, Portis JL (1991) Murine retrovirus-induced spongiform encephalopathy: productive infection of microglia and cerebellar neurons in accelerated CNS disease. Neuron 7: 365-379.
  12. Czub S, Lynch WP, Czub M, Portis JL (1994) Kinetic analysis of spongiform neurodegenerative disease induced by a highly virulent murine retrovirus. Lab Invest 70: 711-723.
  13. Wiley CA, Gardner M (1993) The pathogenesis of murine retroviral infection of the central nervous system. Brain Pathol 3: 123-128.
  14. Gardner MB, Rasheed S, Klement V, Rongey RW, Brown JC, et al. (1976) Lower motor neuron disease in wild mice caused by indigenous type C virus and search for a similar etiology in human amyotrophic lateral sclerosis. UCLA Forum Med Sci 1976: 217-234.
  15. Andrews JM, Gardner MB (1974) Lower motor neuron degeneration associated with type C RNA virus infection in mice: neuropathological features. J Neuropathol Exp Neurol 33: 285-307.
  16. Li Y, Davey RA, Sivaramakrishnan S, Lynch WP (2014) Postinhibitory rebound neurons and networks are disrupted in retrovirus-induced spongiform neurodegeneration. J Neurophysiol 112: 683-704.
  17. Sivaramakrishnan S, Oliver DL (2001) Distinct K currents result in physiologically distinct cell types in the inferior colliculus of the rat. J Neurosci 21: 2861-2877.
  18. Peruzzi D, Sivaramakrishnan S, Oliver DL (2000) Identification of cell types in brain slices of the inferior colliculus.  Neuroscience 101: 403-416.
  19. Sivaramakrishnan S, Sanchez JT, Grimsley CA (2013) High concentrations of divalent cations isolate monosynaptic inputs from local circuits in the auditory midbrain. Front Neural Circuits 7: 175.
  20. Sivaramakrishnan S, Oliver DL (2006) Neuronal responses to lemniscal stimulation in laminar brain slices of the inferior colliculus.  J Assoc Res Otolaryngol 7: 1-14.
  21. Grimsley CA, Sanchez JT, Sivaramakrishnan S (2013) Midbrain local circuits shape sound intensity codes. Front Neural Circuits 7: 174.
  22. Chandrasekaran L, Xiao Y, Sivaramakrishnan S (2013) Functional architecture of the inferior colliculus revealed with voltage-sensitive dyes. Front Neural Circuits 7: 41.
  23. Ylinen A, Soltész I, Bragin A, Penttonen M, Sik A, et al. (1995) Intracellular correlates of hippocampal theta rhythm in identified pyramidal cells, granule cells, and basket cells. Hippocampus 5: 78-90.
  24. Soltesz I, Deschenes M, (1993) Low- and high-frequency membrane potential oscillations during theta activity in CA1 and CA3 pyramidal neurons of the rat hippocampus under ketamine-xylazine anesthesia. J Neurophysiol 70: 97-116.
  25. Sohal VS, Pangratz-Fuehrer S, Rudolph U, Huguenard JR (2006) Intrinsic and synaptic dynamics interact to generate emergent patterns of rhythmic bursting in thalamocortical neurons. J Neurosci 26: 4247-4255.
  26. Selverston AI, Moulins M (1985) Oscillatory neural networks.  Annu Rev Physiol 47: 29-48.
  27. Kuwada S, Batra R, (1999) Coding of sound envelopes by inhibitory rebound in neurons of the superior olivary complex in the unanesthetized rabbit. J Neurosci 19: 2273-2287.
  28. Kiehn O (2006) Locomotor circuits in the mammalian spinal cord.  Annu Rev Neurosci 29: 279-306.
  29. Felix RA 2nd, Fridberger A, Leijon S, Berrebi AS, Magnusson AK (2011) Sound rhythms are encoded by postinhibitory rebound spiking in the superior paraolivary nucleus. J Neurosci 31: 12566-12578.
  30. Dougherty KJ, Zagoraiou L, Satoh D, Rozani I, Doobar S, et al. (2013) Locomotor rhythm generation linked to the output of spinal shox2 excitatory interneurons.  Neuron 80: 920-933.
  31. Dethier J, Drion G, Franci A, Sepulchre R (2015) A positive feedback at the cellular level promotes robustness and modulation at the circuit level. J Neurophysiol 114: 2472-2484.
  32. Wilson JM, Blagovechtchenski E, Brownstone RM (2010) Genetically defined inhibitory neuronsin the mouse spinal cord dorsal horn: a possible source of rhythmic inhibition of motoneurons during fictive locomotion. J Neurosci 30: 1137-1148.
  33. Best J, Park C, Terman D, Wilson C (2007) Transitions between irregular and rhythmic firing patterns in excitatory-inhibitory neuronal networks. J Comput Neurosci 23: 217-235.
  34. Paz JT, Deniau JM, Charpier S (2005) Rhythmic bursting in the cortico-subthalamo-pallidal network during spontaneous genetically determined spike and wave discharges. J Neurosci 25: 2092-2101.
  35. Roberts A, Tunstall MJ, Wolf E (1995) Properties of networks controlling locomotion and significance of voltage dependency of NMDA channels: stimulation study of rhythm generation sustained by positive feedback. J Neurophysiol 73: 485-495.
  36. Mattia D, Hwa GG, Avoli M (1993) Membrane properties of rat subicular neurons in vitro.  J Neurophysiol 70: 1244-1248.
  37. Stanford IM (2003) Independent neuronal oscillators of the rat globus pallidus.  J Neurophysiol 89: 1713-1717.
  38. Li WC, Moult PR (2012) The control of locomotor frequency by excitation and inhibition.  J Neurosci 32: 6220-6230.
  39. Rinzel J (1998) Propagating activity patterns in large-scale inhibitory neuronal networks. Science 279: 1351-1355.
  40. Adhikari MH, Quilichini PP, Roy D, Jirsa V, Bernard C (2012) Brain state dependent postinhibitory rebound in entorhinal cortex interneurons. J Neurosci 32: 6501-6510.
  41. Whyment AD, Wilson JM, Renaud LP, Spanswick D (2004) Activation and integration of bilateral GABA-mediated synaptic inputs in neonatal rat sympathetic preganglionic neurones in vitro. J Physiol 555: 189-203.
  42. Amendola J, Gueritaud JP, Lamotte d'Incamps B, Bories C, Liabeuf S, et al. (2007) Postnatal electrical and morphological abnormalities in lumbar motoneurons from transgenic mouse models of amyotrophic lateral sclerosis. Arch Ital Biol 145: 311-323.
  43. Bories C, Amendola J, Lamotte d'Incamps B, Durand J (2007) Early electrophysiological abnormalities in lumbar motoneurons in a transgenic mouse model of amyotrophic lateral sclerosis. Eur J Neurosci 25: 451-459.
  44. Hodges JR, Davies RR, Xuereb JH, Casey B, Broe M, et al. (2004) Clinicopathological correlates in frontotemporal dementia.  Ann Neurol 56: 399-406.
  45. Gourine AV, Kasymov V, Marina N, Tang F, Figueiredo MF, et al. (2010) Astrocytes control breathing through pH-dependent release of ATP. Science 329: 571-575.
  46. Winograd CD, Clayton D, Ceman S (2008) Expression of fragile X mental retardation protein within the vocal control system of developing and adult male zebra finches. Neuroscience 157: 132-142.
  47. Perkel DH, Mulloney B (1974) Motor pattern production in reciprocally inhibitory neurons exhibiting postinhibitory rebound. Science 185: 181-183.
  48. Iftinca MC, Zamponi GW (2009) Regulation of neuronal T-type calcium channels.  Trends Pharmacol Sci 30: 32-40.
  49. Liu S, Shipley MT (2008) Intrinsic conductances actively shape excitatory and inhibitory postsynaptic responses in olfactory bulb external tufted cells. J Neurosci 28: 10311-10322.
  50. Fan YP, Horn EM, Waldrop TG (2000) Biophysical characterization of rat caudal hypothalamic neurons: calcium channel contribution to excitability. J Neurophysiol 84: 2896-2903.
  51. Palop JJ (2003) Neuronal depletion of calcium-dependent proteins in the dentate gyrus is tightly linked to Alzheimer's disease-related cognitive deficits. Proc Natl Acad Sci U S A 100: 9572-9577.
  52. Hegedus J, Putman CT, Gordon T (2007) Time course of preferential motor unit loss in the SOD1 G93A mouse model of amyotrophic lateral sclerosis.  Neurobiol Dis 28: 154-164.
  53. Comley L, Allodi I, Nichterwitz S, Nizzardo M, Simone C, et al. (2015) Motor neurons with differential vulnerability to degeneration show distinct protein signatures in health and ALS.  Neuroscience 291: 216-229.
  54. Zettel ML, Frisina RD, Haider SE, O'Neill WE (1997) Age-related changes in calbindin D-28k and calretinin immunoreactivity in the inferior colliculus of CBA/CaJ and C57Bl/6 mice.  J Comp Neurol 386: 92-110.
  55. Idrizbegovic E, Bogdanovic N, Canlon B (1999) Sound stimulation increases calcium-binding protein immunoreactivity in the inferior colliculus in mice. Neurosci Lett 259: 49-52.
  56. Bäurle J, Hoshi M, Grüsser-Cornehls U (1998) Dependence of parvalbumin expression on Purkinje cell input in the deep cerebellar nuclei.  J Comp Neurol 392: 499-514.
  57. Bastianelli E (2003) Distribution of calcium-binding proteins in the cerebellum.  Cerebellum 2: 242-262.
  58. Gall D, Roussel C, Nieus T, Cheron G, Servais L, et al. (2005) Role of calcium binding proteins in the control of cerebellar granule cell neuronal excitability: experimental and modeling studies. Prog Brain Res 148: 321-328.
  59. Cheron G, Servais L, Dan B, Gall D, Roussel C, et al. (2005) Fast oscillation in the cerebellar cortex of calcium binding protein-deficient mice: a new sensorimotor arrest rhythm. Prog Brain Res 148: 165-180.
  60. Li Y, Cardona SM, Traister RS, Lynch WP (2011) Retrovirus-induced spongiform neurodegeneration is mediated by unique central nervous system viral targeting and expression of env alone. J Virol 85: 2060-2078.
  61. Lynch WP, Snyder EY, Qualtiere L, Portis JL, Sharpe AH (1996) Late virus replication events in microglia are required for neurovirulent retrovirus-induced spongiform neurodegeneration: evidence from neural progenitor-derived chimeric mouse brains. J Virol 70: 8896-8907.
  62. Lynch WP, Sharpe AH, Snyder EY (1999) Neural stem cells as engraftable packaging lines can mediate gene delivery to microglia: evidence from studying retroviral env-related neurodegeneration. J Virol 73: 6841-6851.
  63. Robertson SJ, Hasenkrug KJ, Chesebro B, Portis JL (1997) Neurologic disease induced by polytropic murine retroviruses: neurovirulence determined by efficiency of spread to microglial cells. J Virol 71: 5287-5294.
  64. Li Y, Dunphy JM, Pedraza CE, Lynch CR, Cardona SM, et al. (2016) Ecotropic Murine Leukemia Virus Infection of Glial Progenitors Interferes with Oligodendrocyte Differentiation: Implications for Neurovirulence. J Virol 90: 3385-3399.
  65. Gravel C, Kay DG, Jolicoeur P (1993) Identification of the infected target cell type in spongiform myeloencephalopathy induced by the neurotropic Cas-Br-E murine leukemia virus. J Virol 67: 6648-6658.
  66. Clase AC, Dimcheff DE, Favara C, Dorward D, McAtee FJ, et al. (2006) Oligodendrocytes are a major target of the toxicity of spongiogenic murine retroviruses. Am J Pathol 169: 1026-1038.
  67. Nagra RM, Masliah E, Wiley CA (1993) Synaptic and dendritic pathology in murine retroviral encephalitis.  Exp Neurol 124: 283-288.
  68. Nagra RM, Burrola PG, Wiley CA (1992) Development of spongiform encephalopathy in retroviral infected mice.  Lab Invest 66: 292-302.
  69. Larson VA, Zhang Y, Bergles DE (2016) Electrophysiological properties of NG2(+) cells: Matching physiological studies with gene expression profiles. Brain Res 1638: 138-160.
  70. De Biase LM, Nishiyama A, Bergles DE (2010) Excitability and synaptic communication within the oligodendrocyte lineage.  J Neurosci 30: 3600-3611.
  71. Hill RA, Nishiyama A (2014) NG2 cells (polydendrocytes): listeners to the neural network with diverse properties.  Glia 62: 1195-1210.
  72. Nishiyama A, Komitova M, Suzuki R, Zhu X (2009) Polydendrocytes (NG2 cells): multifunctional cells with lineage plasticity.  Nat Rev Neurosci 10: 9-22.
  73. Morquette P, Verdier D, Kadala A, Féthière J, Philippe AG, et al. (2015) An astrocyte-dependent mechanism for neuronal rhythmogenesis.  Nat Neurosci 18: 844-854.
  74. Eugenin EA, Clements JE, Zink MC, Berman JW (2011) Human immunodeficiency virus infection of human astrocytes disrupts blood-brain barrier integrity by a gap junction-dependent mechanism. J Neurosci 31: 9456-9465.
  75. Eugenin EA, Berman JW (2007) Gap junctions mediate human immunodeficiency virus-bystander killing in astrocytes. J Neurosci 27: 12844-12850.
  76. Arbour D, Tremblay E, Martineau É, Julien JP, Robitaille R (2015) Early and persistent abnormal decoding by glial cells at the neuromuscular junction in an ALS model.  J Neurosci 35: 688-706.
  77. Sun W, Matthews EA, Nicolas V, Schoch S, Dietrich D (2016) NG2 glial cells integrate synaptic input in global and dendritic calcium signals.  Elife 5: e16262.
  78. Hughes EG, Kang SH, Fukaya M, Bergles DE (2013) Oligodendrocyte progenitors balance growth with self-repulsion to achieve homeostasis in the adult brain.  Nat Neurosci 16: 668-676.
  79. Lynch WP, Brown WJ, Spangrude GJ, Portis JL (1994) Microglial infection by a neurovirulent murine retrovirus results in defective processing of envelope protein and intracellular budding of virus particles. J Virol 68: 3401-3419.
  80. Dimcheff DE (2006) Gene expression profiling of microglia infected by a highly neurovirulent murine leukemia virus: implications for neuropathogenesis. Retrovirology 3: 26.
  81. Morey MK, Wiley CA (1990) Immunohistochemical localization of neurotropic ecotropic murine leukemia virus in moribund mice. Virology 178: 104-112.
  82. Ng FS, Tangredi MM, Jackson FR (2011) Glial cells physiologically modulate clock neurons and circadian behavior in a calcium-dependent manner. Curr Biol 21: 625-634.
  83. Xiang P (2015) The activation of NG2 expressing cells is downstream to microglial reaction and mediated by the transforming growth factor beta 1. J Neuroimmunol 279: 50-63.
  84. Lynch WP, Robertson SJ, Portis JL (1995) Induction of focal spongiform neurodegeneration in developmentally resistant mice by implantation of murine retrovirus-infected microglia. J Virol 69: 1408-1419.
  85. Eyo UB, Wu LJ (2013) Bidirectional microglia-neuron communication in the healthy brain.  Neural Plast 2013: 456857.
  86. Pascual O, Casper KB, Kubera C, Zhang J, Revilla-Sanchez R, et al. (2005) Astrocytic purinergic signaling coordinates synaptic networks.  Science 310: 113-116.
  87. Pascual O, Ben Achour S, Rostaing P, Triller A, Bessis A (2012) Microglia activation triggers astrocyte-mediated modulation of excitatory neurotransmission. Proc Natl Acad Sci U S A 109: E197-205.
  88. Song H, Hayes JA, Vann NC, Drew LaMar M, Del Negro CA (2015) Mechanisms Leading to Rhythm Cessation in the Respiratory PreBotzinger Complex Due to Piecewise Cumulative Neuronal Deletions(1,2,3). eNeuro.
  89. Kobayashi R, Nishimaru H, Nishijo H (2016) Estimation of excitatory and inhibitory synaptic conductance variations in motoneurons during locomotor-like rhythmic activity. Neuroscience 335: 72-81.
  90. Tashiro S, Nishimura S, Iwai H, Sugai K, Zhang L, et al. (2016) Functional Recovery from Neural Stem/Progenitor Cell Transplantation Combined with Treadmill Training in Mice with Chronic Spinal Cord Injury.  Sci Rep 6: 30898.
  91. Jahnsen H (1986) Extracellular activation and membrane conductances of neurones in the guinea-pig deep cerebellar nuclei in vitro. J Physiol 372: 149-168.
  92. Pinault D, Deschenes M (1992) The origin of rhythmic fast subthreshold depolarizations in thalamic relay cells of rats under urethane anaesthesia. Brain Res 595: 295-300.
  93. Perron H, Dougier-Reynaud HL, Lomparski C, Popa I, Firouzi R, et al. (2013) Human endogenous retrovirus protein activates innate immunity and promotes experimental allergic encephalomyelitis in mice. PLoS One 8: e80128.
  94. Kane M, Case LK, Wang C, Yurkovetskiy L, Dikiy S, et al. (2011) Innate immune sensing of retroviral infection via Toll-like receptor 7 occurs upon viral entry.  Immunity 35: 135-145.
  95. Jude BA, Pobezinskaya Y, Bishop J, Parke S, Medzhitov RM, et al. (2003) Subversion of the innate immune system by a retrovirus.  Nat Immunol 4: 573-578.
  96. Perron H, Germi R, Bernard C, Garcia-Montojo M, Deluen C, et al. (2012) Human endogenous retrovirus type W envelope expression in blood and brain cells provides new insights into multiple sclerosis disease. Mult Scler 18: 1721-1736.
  97. Antony JM, van Marle G, Opii W, Butterfield DA, Mallet F, et al. (2004) Human endogenous retrovirus glycoprotein-mediated induction of redox reactants causes oligodendrocyte death and demyelination. Nat Neurosci 7: 1088-1095.
  98. Nexø BA, Christensen T, Frederiksen J, Møller-Larsen A, Oturai AB, et al. (2011) The etiology of multiple sclerosis: genetic evidence for the involvement of the human endogenous retrovirus HERV-Fc1. PLoS One 6: e16652.
  99. Laska MJ, Brudeka T, Nissen KK, Christensen K, Møller-Larsen A, et al. (2012) Expression of HERV-Fc, a human endogenous retrovirus, is increased in patients with active multiple sclerosis. J Virol 86: 3713-3722.
  100. de la Hera B, Varadé J, García-Montojo M, Alcina A, Fedetz M, et al. (2014) Human endogenous retrovirus HERV-Fc1 association with multiple sclerosis susceptibility: a meta-analysis. PLoS One 9: e90182.
  101. Bhat RK, Ellestad KK, Wheatley BM, Warren R, Holt RA, et al. (2011) Age- and disease-dependent HERV-W envelope allelic variation in brain: association with neuroimmune gene expression.  PLoS One 6: e19176.
  102. Kremer D, Schichel T, Förster M, Tzekova N, Bernard C, et al. (2013) Human endogenous retrovirus type W envelope protein inhibits oligodendroglial precursor cell differentiation. Ann Neurol 74: 721-732.
  103. Douville R, Liu J, Rothstein J, Nath A (2011) Identification of active loci of a human endogenous retrovirus in neurons of patients with amyotrophic lateral sclerosis. Ann Neurol 69: 141-151.
  104. Li W, Lee MH, Henderson L, Tyagi R, Bachani M, et al. (2015) Human endogenous retrovirus-K contributes to motor neuron disease.  Sci Transl Med 7: 307ra153.
Citation: Sivaramakrishnan S, Lynch WP (2017) Rebound from Inhibition: Self-Correction against Neurodegeneration?. J Clin Cell Immunol 8:492.

Copyright: © 2017 Sivaramakrishnan S, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.