Cerebellar Dysfunction in Demyelinating Disorders

Our Center was the first to demonstrate dysregulated ion channel behavior in MS, identifying channelopathy as yet another pathology associated with MS, in addition to demyelination and axonal degeneration. These studies, performed using rodent EAE models of MS as well as human MS tissue, demonstrated that sodium channel Nav1.8, which is normally present only in the spinal sensory neurons, is produced in the Purkinje neurons within the cerebellum-region of the brain that controls balance and coordination in MS.

We the demonstrated that the presence of sodium channel Nav1.8 within the cerebellar Purkinje cells significantly alters their firing pattern and therefore their behavior, both in vivo and in cultured cells (Renganathan et al., 2003, Saab et al., 2004). We also demonstrated an up-regulation of annexinII/p11, a binding partner of Nav1.8, in Purkinje cells in EAE and MS (Craner et al., NeuroReport 2003). This is an important finding because annexinII/p11 promotes insertion of functional Nav1.8 channels within the neuronal cell membrane and therefore aids in its function. We demonstrated a similar upregulation of Nav1.8 within retinal ganglion cells, which give rise to optic nerve axons that are commonly affected in MS (Craner et al., Brain 2003). Our studies also demonstrate that the time-course of upregulation of Nav1.8 sodium channels within Purkinje neurons correlates with disease progression in EAE.

Taken together, our studies have identified a previously unrecognized "mis-tuning" of nerve cells in MS, opening up the possibility of using molecular pharmacology to "retune" the central nervous system in MS. Specifically these studies on the contribution of dysregulated ion channel expression to clinical symptoms in MS will enable identification of strategies to block it, and to ultimately develop new therapies that will improve balance, coordination and visual function in people with MS.

Renganathan M, Gelderblom M, Black JA, Waxman SG. Expression of Nav1.8 sodium channels perturbs the firing patterns of cerebellar Purkinje cells. Brain Res. 2003 Jan 10; 959(2):235-42.

Saab CY, Craner MJ, Kataoka Y, Waxman SG. Abnormal Purkinje cell activity in vivo in experimental allergic encephalomyelitis. Exp Brain Res. 2004 Sep; 158(1):1-8.

Craner MJ, Lo AC, Black JA, Baker D, Newcombe J, Cuzner ML, Waxman SG. Annexin II/p11 is up-regulated in Purkinje cells in EAE and MS. Neuroreport. 2003 Mar 24; 14(4):555-8.

Craner MJ, Kataoka Y, Lo AC, Black JA, Baker D, Waxman SG. Temporal course of upregulation of Na(v)1.8 in Purkinje neurons parallels the progression of clinical deficit in experimental allergic encephalomyelitis. J Neuropathol Exp Neurol. 2003 Sep; 62(9):968-75.

Craner MJ, Lo AC, Black JA, Waxman SG. Abnormal sodium channel distribution in optic nerve axons in a model of inflammatory demyelination. Brain. 2003 Jul; 126(Pt 7):1552-61.

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