Impaired eye-blink conditioning in waggler, a mutant mouse with cerebellar BDNF deficiency

Abstract

In addition to their trophic functions, neurotrophins are also implicated in synaptic modulation and learning and memory. Although gene knockout techniques have been used widely in studying the roles of neurotrophins at molecular and cellular levels, behavioral studies using neurotrophin knockouts are limited by the early-onset lethality and various sensory deficits associated with the gene knockout mice. In the present study, we found that in a spontaneous mutant mouse, waggler, the expression of brain-derived neurotrophic factor (BDNF) was selectively absent in the cerebellar granule cells. The cytoarchitecture of the waggler cerebellum appeared to be normal at the light microscope level. The mutant mice exhibited no sensory deficits to auditory stimuli or heat-induced pain. However, they were massively impaired in classic eye-blink conditioning. These results suggest that BDNF may have a role in normal cerebellar neuronal function, which, in turn, is essential for classic eye-blink conditioning.

Figure 1

Expression patterns of BDNF mRNA in adult brains of wild-type (A) and waggler mice (B). The only noticeable difference is the absence of BDNF mRNA in the waggler cerebellar granule cell layer.

Figure 2

Sagittal sections of the cerebellar cortex (A, wild-type; B, waggler; 40× objectives) and coronal sections of the cerebellar interpositus nucleus (C, wild-type; D, waggler; 20×).

Figure 3

Coronal brain sections of the wild-type and waggler mice. (A) Cerebellar deep nuclei (5× objectives); (B) inferior olive (10×); (C) basal pontine gray (5×); (D) red nucleus (10×); (E) cochlear nuclei (5×); (F), hippocampus (5×).

Figure 4

Onset latencies of heat-induced tail flicks as an index of pain perception. It took a similar amount of time for both wild-type (solid bar) and waggler (open bar) mice to feel the 51°C hot plate-induced pain and to start tail flicks.

Figure 5

(A,B) The 10-trial summary of tone-induced neuronal responses recorded from auditory cortex of wild-type (A) and waggler (B) mice. (C) Tone fear conditioning. Wild-type (•) and waggler (█) showed no difference in freezing percentage after three foot shocks or during the first minute of the tone test.

Figure 6

Percent CR (top) and UR (bottom) amplitudes exhibited by wild-type (•) and waggler (█) mice. The percent CRs were calculated using CS–US paired trials.

Figure 7

Percent CRs of the wild-type (•) and waggler (█) mice during acquisition and extinction phases. The percent CRs were calculated using CS-alone trials.

Figure 8

The onset (A,B) and peak (C,D) latencies exhibited by wild-type (solid bars) and waggler (open bars) mice. Both numbers of occurrence (A,C) and occurring frequencies (B,D) are presented.