In healthy adults, activation of γ-aminobutyric acid (GABA) A and glycine receptors inhibits neurons as a result of low intracellular chloride concentration ([Cl -] i ), which is maintained by the potassium-chloride cotransporter KCC2. A reduction of KCC2 expression or function is implicated in the pathogenesis of several neurological disorders, including spasticity and chronic pain following spinal cord injury (SCI). Given the critical role of KCC2 in regulating the strength and robustness of inhibition, identifying tools that may increase KCC2 function and, hence, restore endogenous inhibition in pathological conditions is of particular importance. We show that activation of 5-hydroxytryptamine (5-HT) type 2A receptors to serotonin hyperpolarizes the reversal potential of inhibitory postsynaptic potentials (IPSPs), E IPSP , in spinal motoneurons, increases the cell membrane expression of KCC2 and both restores endogenous inhibition and reduces spasticity after SCI in rats. Up-regulation of KCC2 function by targeting 5-HT 2A receptors, therefore, has therapeutic potential in the treatment of neurological disorders involving altered chloride homeostasis. However, these receptors have been implicated in several psychiatric disorders, and their effects on pain processing are controversial, highlighting the need to further investigate the potential systemic effects of specific 5-HT 2A R agonists, such as (4-bromo-3,6-dimethoxybenzocyclobuten-1-yl)methylamine hydrobromide (TCB-2). ] i (depolarizing shift of the chloride equilibrium potential, E Cl ) dramatically compromises the inhibitory control of firing rate and excitatory inputs (5-7). Given the role of KCC2 in regulating the strength of inhibitory synaptic transmission, identifying tools that may increase KCC2 function and, hence, restore endogenous inhibition in pathological conditions is of particular importance.Spasticity is a disabling complication affecting individuals with spinal cord injury (SCI) and is characterized by a velocity-dependent increase in muscle tone resulting from hyperexcitable stretch reflexes, spasms, and hypersensitivity to normally innocuous sensory stimulations (8, 9). Down-regulation of KCC2 after SCI in rats is implicated in the development of spasticity (10) and chronic pain (11,12). Notably, the expression of KCC2 in the motoneuron membrane is reduced, and, concomitantly, the density of cytoplasmic clusters is higher, suggesting that the surface stability of the transporter is reduced in these pathological conditions (10).Mounting evidence indicates that phosphorylation of KCC2 in the C-terminal intracellular domain dynamically regulates its activity and surface expression (1). In particular, phosphorylation by protein kinase (PK)C, enhances KCC2 activity and reduces endocytosis (13). Interestingly, activation of 5-hydroxytryptamine type 2 receptors (5-HT 2 Rs) to serotonin stimulates PKC and strengthens the left-right alternation of motor bursts observed during locomotion (14-16), which rely on reciprocal inhibition (17, 18). ...

Reactive cell proliferation occurs rapidly in the cat vestibular nuclei (VN) after unilateral vestibular neurectomy (UVN) and has been reported to facilitate the recovery of posturo-locomotor functions. Interestingly, whereas animals experience impairments for several weeks, extraordinary plasticity mechanisms take place in the local microenvironment of the VN: newborn cells survive and acquire different phenotypes, such as microglia, astrocytes, or GABAergic neurons, whereas animals eventually recover completely from their lesion-induced deficits. Because brain-derived neurotrophic factor (BDNF) can modulate vestibular functional recovery and neurogenesis in mammals, in this study, we examined the effect of BDNF chronic intracerebroventricular infusion versus K252a (a Trk receptor antagonist) in our UVN model. Results showed that long-term intracerebroventricular infusion of BDNF accelerated the restoration of vestibular functions and significantly increased UVN-induced neurogenesis, whereas K252a blocked that effect and drastically delayed and prevented the complete restoration of vestibular functions. Further, because the level of excitability in the deafferented VN is correlated with behavioral recovery, we examined the state of neuronal excitability using two specific markers: the cation-chloride cotransporter KCC2 (which determines the hyperpolarizing action of GABA) and GABA A receptors. We report for the first time that, during an early time window after UVN, significant BDNF-dependent remodeling of excitability markers occurs in the brainstem. These data suggest that GABA acquires a transient depolarizing action during recovery from UVN, which potentiates the observed reactive neurogenesis and accelerates vestibular functional recovery. These findings suggest that BDNF and/or KCC2 could represent novel treatment strategies for vestibular pathologies.