Abnormal Climbing Fiber-Purkinje Cell Synaptic Connections in the Essential Tremor Cerebellum (P3.011)

OBJECTIVE: The aim of the present study was to examine the density and distribution of climbing fiber-Purkinje cell (CF-PC) synapses using postmortem cerebellar tissue of essential tremor (ET) cases and controls. BACKGROUND: Structural changes in PCs have been identified in the ET cerebellum, although the mechanisms that underlie these changes remain poorly understood. CFs provide one of the major excitatory inputs to PCs, and CF-PC connections are essential for normal cerebellar-mediated motor control. The distribution of CF-PC synapses on PC dendrites is dynamically regulated and may be altered in disease states. DESIGN/METHODS: Using vesicular glutamate transporter type 2 immunohistochemistry, we labeled CF-PC synapses of 12 ET cases and 13 age-matched controls from the New York Brain Bank. RESULTS: Normally, CFs form synapses mainly on the thick, proximal PC dendrites in the inner portion of the molecular layer, whereas parallel fibers form synapses on the thin, distal PC spiny branchlets. We observed that, compared with controls, ET cases had decreased CF-PC synaptic density 25.88 ± 1.45 VGlut2 puncta/ 100μm of CFs in ET cases vs. 33.46 ± 4.33 VGlut2 puncta/100μm of CFs in controls, p<0.001), more CFs extending to the outer portion of the molecular layer (2.39 ± 0.77 in ET cases vs. 1.27 ± 0.45 in controls, p<0.001), and more CF-PC synapses on the thin PC spiny branchlets (26[percnt] ± 12[percnt] in ET cases vs. 12[percnt] ± 7[percnt] in controls, p=0.003). Interestingly, in ET, the increased distribution of CF-PC synapses on the thin PC branchlets was inversely associated with clinical tremor severity (r=-0.88, p=0.003), indicating a close relationship between the altered distribution of CF-PC connections and tremor. CONCLUSIONS: These findings suggest that abnormal CF-PC connections could be of importance in the pathogenesis of ET. Study Supported by: NINDS #K08 NS08738, American Brain Foundation Research Fellowship, and International Essential Tremor Foundation Disclosure: Dr. Kuo has nothing to disclose. Dr. Lin has nothing to disclose. Dr. Louis has nothing to disclose. Dr. Faust has nothing to disclose. Dr. Koeppen has nothing to disclose. Dr. Vonsattel has nothing to disclose.