Journal club: An increased extrasynaptic NMDA tone inhibits A-type K+ current and increases excitability of hypothalamic neurosecretory neurons in hypertensive rats.

by Meng Zhang, Vinicia C. Bianchardi and Javier E. Stern
DOI: 10.1113/JP274327

In this paper the authors tried to elucidate the mechanism of how the magnocellular neurosecretory neurons become hyperexcitable under pathological condition that could lead to high blood pressure and heart failure.

   Magnocellular neurosecretory cells (MNCs) in hypothalamus release vasopressin and oxytocin, which control fluid balance, and cardio-vascular and reproductive homeostasis. The MNC activity is fine-tuned by intrinsic membrane property, by extrasynaptic inputs, and by the activity of neighbouring astrocytes. MNCs have A-current, which pulls down MNCs from firing action potentials.
   In this study, the authors showed that the activation of eNMDARs inhibited A-current in sham MNCs, but not in MNCs from renovascular hypertensive (RVH) rats. However, neither the exogenously evoked NMDA current nor the expression of NMDAR subunits were altered in RVH rats.  Instead, a larger endogenous glutamate tone, which was not due to blunted glutamate transport activity, led to the sustained activation of eNMDARs. This tonically inhibited A-current and contributed in turn to higher firing activity in RVH rats.

   In this study, they did not show the inactivation curve for the A-current. If I were a referee, I would ask them to show it, because the Glu tone should act very slowly. A-current can inactivated under such condition.

   So, the basal Glu level appears to be very important in regulating the homeostatic functions. It might not be just in the brain. If the extrasynaptic GluRs play similar roles in other nervous system, I can speculate that chronic consumption of MSG might have some bad effects on the peripheral nervous systems such as those controlling guts.

Homeostatic synapse-driven membrane plasticity in nucleus accumbens neurons

By Ishikawa,M.; Mu,P.; Moyer,J.T.; Wolf,J.A.; Quock,R.M.; Davies,N.M.; Hu,X.T.; Schluter,O.M.; Dong,Y.


Abstract:
- Homeostatic mechanisms balances the input-output/synapse-membrane interaction at nucleus accumbens neurons.
- Studies on nucleus accumbens (NAc) neurons revealed a novel form of synapse-to-membrane homeostatic regulation (hSMP), homeostatic synapse-driven membrane plasticity (hSMP).
- Through hSMP, NAc neurons adjusted their membrane excitability to functionally compensate for basal shifts in excitatory synaptic input.
- hSMP is triggered by synaptic NMDA receptors.

Introduction:- Homeostatic plasticity is an important cellular mechanism through which neurons use the neuroplasticity mechinery to maintain stable functional output in an ever-changing internal and external environment (Turrigiano and Nelson, 2004).
- The functional output of a neuron relies on dynamic integration of synaptic inputs and intrinsic membrane excitability.
- It has long been known that homeostatic plasticity can occur independently at either synapses (Turrigiano and Nelson, 2004) or the membrane excitability (Zhang and Linden, 2003).

Results:
- hSMP in NAc slice cultures: NAc mediam spiny neuron (MSNs) increased excitability in slice culture.
- NMDA receptor mediates hSMP. DCS (D-cycloserine).
- hSMP in acute brain slices.
- Synapse-specific hSMP.
- SK channels mediate the expression of hSMP.
- Implication of hSMP in cocaine -induced membrane adaptation.

PLASTICITY OF THE SPINAL NEURAL CIRCUITRY AFTER INJURY

By V. Reggie Edgerton, Niranjala J.K. Tillakaratne, Allison J. Bigbee, Ray D. de Leon, and Roland R. Roy

- A high level of functional recovery can be achieved following a complete spinal cord injury (SCI).
- The level of recovery in motor function is defined by the level and types of motor training or experience following the injury (Edgerton et al. 2001a, Wernig et al. 1995).

- Insight into the mechanisms of recovery and motor learning depends on a basic understanding of
the neural control of motor functions in the uninjured compared to the injured nervous system.


AUTOMATICITY IN POSTURE AND LOCOMOTION: SOME BASIC NEUROBIOLOGICAL PRINCIPLES OF MOTOR CONTROL BEFORE AND AFTER SCI
- Evolutionary learning in shaping the mammalian neural systems that control posture and locomotion.
- The automaticity within the spinal cord becomes even more critical for the CPG circuitry to successfully process sensory inputs.

Supraspinal Control of Posture and Locomtion
- The specific control features of each of the descending spinal tracts in controlling locomotion are poorly understood.

Spinal Control of Posture and Locomotion
1) CPG
2) SENSORY INPUT
- We propose that the spinal cord processes and interprets proprioception in a manner similar to how our visual system processes information (pattern recognition?).
- At any instant, the spinal cord receives an ensemble of information from all receptors throughout the body that signals a proprioceptive "image" that represents time and space.
- The importance of the CPG is not simply its ability to generate repetitive cycles, but also to receive, interpret, and predict the appropriate sequences of actions during any part of the step cycle, i.e., "state-dependence."
- The injured spinal cord interprets sensory changes in load and speed
- SCI patients can voluntarily initiate locomotion

3) THE INJURED SPINAL CORD IS AN "ALTERED" SPINAL CORD
- The spinal cord processes input and generates motor output in a different manner as a result of injury-related adaptations.
- Spasticity is a sign of activity in the spinal circuitry


MOTOR OUTPUT IS ENHANCED BY REPETITIVE TRAINING

Chronic Motor Training Modulates Spinal Plasticity to Enhance Motor Output After SCI
- Experiments with spinal cats using chronic locomotor training paradigms sugget that the ability to learn and successfully perform a motor task is dependent on repetitive practice.
- The functional state of the cord is shaped by specific locomotor training regimes.
- Although the mechanisms underlying locomotor training-enhanced plasticity is not well understood, it is clear that the physiological state of the cord can be affected by activity-dependent processes that can influence its ability to learn and perform a specified motor behavior.

The Spinal Cord Can Respond to Novel, Acute Perturbation
- An example of an object placed in front of a spinal cat stepping on a treadmill, a learning and memory-type phenomenon may be taking place ("smartness" of the spinal cord).
- Spinal cord is "solving" problems in real time based on the continually changing state of incoming peripehral information to elicit a nearly constant behavior, even though the means to the endpoint differ.
- These studies imply that spinal learning can occur in a very short period of time, and a type of memory trace allows for quicker adaptation upon reexposure to a given perturbation (Liu et al., 2003).
- The underlying cellular mechanisms are unknown.
- Hippocampal learning-like phenomena can occur in the spinal cord, but largely unknown.

Biochemical and Phamacological Evidence for Spinal Cord Plasticity After Injury
- The functinally recovered spinal animals showed no evidence of regeneration of descending pathways (Joynes et al. 1999) or showed minimal changes in hindlimb skeletal muscle properties to account for the recoery characteristics, the functinal behavior exhibited by these animals must have been mediated by the plasticity in existing spinal pathways.
- This plasticity may occur at any of many spinal cord regions or cell types such as motoneurons, premotor pattern-generating neurons, and/or nonneuronal celly types.
- There could also be anatomically altered synaptic connections, increased active zones of synapses, altered sensitivities of neurotoransmitter receptors, or altered pruduction of neurotransmitters.
- Data showed a significant role for these neurotransmitter systems in facilitating locomotor activity and thus suggest that these agents might be useful for inducing locomotion in SCI animals.
- Administration of 5-HT, its precursor 5-HTP, or the 5-HT agonists are also effective in improving locomotion in cats (Barbeau & Rossignol 1990, 1991) and rats (Feraboli-Lohnherr et al. 1999, Kim et al. 2001).
- The mechanism is unknown.
- The improvement of motor recovery upon the administration of of strychnine or bicuculline may occur by facilitating neuronal excitation by blocking the abnormally high levels of general inhibition resulting from a complete SCI (de Leon et al. 1999b).
- Nontrained spinal rats have increased GABA synthetic enzyme GAD67 and glycine and GABA_A receptors in the lumbar spinal cord, whereas step-trained spinal rats have near-normal levels (Edgerton et al. 2001a, Tillakaratne et al. 2000).
- Training spinal cats to weight-bear also appears to reduce GABA signaling in some spinal interneurons.
- The amount of these enzymes depends on the type of training.
- These finding suggest that the inability of stand-trained spinal animals to step is closely linked to an elevated level of inhibition of flexor motor pools.
- The elevated level of a GABA_A receptor subunit returns toward nearly undetectable control levels after six weeks of step training.
- Plasticity of spinal circuit may also be mediated by activity-dependent induction of neurotrophins.

Effects of Electrical Stimulation on Locomotor Recovery After SCI


HUMAN SCI: A PERSPECTIVE

Treadmill Training and the Recovery of Walking Ability After SCI

Use of Pharmacological Therapies in Enhancing Walking after SCI


CONCLUSION
- Training to stand improves standing ability and training to step improves stepping ability.
- One of the biochemical consequences of a complete SCI is an upregulation of inhibitory neurotransmitter systems, and step training reverses this effect.
- Physiological and biochemical state of the spinal conrd will affect how it respond to any given therapeutic intervention.