Heterozygous knock-out mice for brain-derived neurotrophic factor show a pathway-specific impairment of long-term potentiation but normal critical period for monocular deprivation

Abstract

Genetic deletion of a single allele of the BDNF gene affects hippocampal LTP and causes several behavioral phenotypes, including deficits in spatial learning. In the developing visual cortex, overexpression of BDNF accelerates the time course of the critical period for monocular deprivation (MD), and exogenous administration of BDNF alters the outcome of MD. We asked whether reduced levels of BDNF could affect visual cortex plasticity by studying long-term potentiation (LTP) induction and the effects of MD in heterozygous BDNF knock-out mice. We found that theta burst stimulation that induced LTP in the layer IV-III pathway of wild-type (wt) mice caused only a transient potentiation in BDNF+/- mice, and that this potentiation vanished in 25 min. In contrast, LTP elicited by stimulation of the white matter (WM), a form of LTP that can be induced only during the critical period, occurred normally in wt and BDNF+/- mice. The effects of MD during the critical period were similar in wt and BDNF+/- mice, indicating that layer IV-evoked, layer III LTP is not required for ocular dominance plasticity. We then asked whether reduction of cortical BDNF levels could prolong the critical period for MD and for the WM-evoked, layer III LTP induction. We found that in adult BDNF+/- mice, WM-evoked, layer III LTP was not inducible, and that the critical period for MD terminated normally. We conclude that deletion of one copy of the BDNF gene selectively impairs LTP of the layer IV-III pathway but does not alter ocular dominance plasticity.

Fig. 1.

BDNF+/− mice show impaired layer IV-evoked but normal WM-evoked layer III LTP. A–C (layers IV–III):A, Average time course of layer III field potential amplitude before and after TBS of layer IV in wt mice (n = 16 slices; 6 mice) and BDNF+/− mice (n = 10 slices; 6 mice). In contrast to wt animals, in which LTP persists for at least 30 min, BDNF+/− animals show a fast decay of response amplitude starting 5 min after TBS and returning to baseline values within 25 min. B, Average of 10 traces recorded from a wt and a BDNF+/− slice before, 3 min after TBS (BDNF+/−), and 25 min after TBS. C, Average and single cases of LTP in wt and BDNF+/− slices 25 min after TBS. BDNF+/− slices significantly differ from wt, showing no LTP at this time (t test). D–F (WM–layer III):D, Average time course of layer III field potential amplitudes before and after TBS of WM in wt mice (n= 6 slices; 2 mice) and BDNF+/− mice (n = 9 slices; 4 mice). Both experimental groups exhibit an LTP of synaptic responses after TBS. E, Average of 10 traces recorded from a wt and a BDNF+/− slice before and 25 min after TBS.F, Average and single cases of LTP in wt and BDNF+/− slices 25 min after TBS. There is no significant difference between the two experimental groups (t test). Solid linesrepresent prebaseline amplitude. Dashed lines show pre-TBS peak level.

Fig. 2.

OD plasticity during the critical period is normal in BDNF+/− mice. A, OD distribution of normal wt mice. The CBI indicates a distribution bias in favor of the contralateral eye. Brief MD (4–5 d) beginning at P26 induces a strong OD shift toward the nondeprived eye in P26 MD wt mice (B) as well as in P26 MD BDNF+/− mice (C). D, Scatterplot of single animal CBIs. Left, P26 MD wt mice; right, P26 MD BDNF+/− mice; shaded region, range of normal adult wt mice. One-way ANOVA shows a significant difference (p = 0.012) between the three groups; thepost hoc Tukey test reveals a significant difference between normal adult and P26 MD wt (p = 0.029) or BDNF+/− (p = 0.006) mice but not between P26 MD wt and P26 MD BDNF+/− mice.

Fig. 3.

WM-evoked, layer III LTP is normal in adult BDNF+/− mice. A, Average time course of layer III field potential amplitude before and after TBS in wt mivr (n = 10 slices; 3 mice) and BDNF+/− mice (n = 10 slices; 4 mice). The field potential amplitude remained at pre-TBS levels in both experimental groups.B, Average of 10 traces recorded from a wt and a BDNF+/− slice before and 25 min after TBS. C, Average and single cases of LTP in wt and BDNF+/− slices 25 min after TBS. There is no significant difference between the two experimental groups (t test). Solid lines represent prebaseline amplitude. Dashed lines show pre-TBS peak level.

Fig. 4.

The critical period is normal in BDNF+/− mice. A, In adult wt mice (older than P51), MD does not induce an OD shift. B, In adult BDNF+/− mice (older than P70), MD is also ineffective in inducing an OD shift.C, CBIs of single animals. Left, Adult MD wt mice; right, adult MD BDNF+/− mice; shaded region, nondeprived mice. No significant difference is present between the three groups (one-way ANOVA). D, Developmental regulation of MD effects in wt and BDNF+/− mice. CBIs of wt and BDNF+/− mice monocularly deprived at different ages (P26, P35, P42, adult) for 4–5 d are shown. Both genotypes exhibit the same sensitivity to MD during the critical period, become increasingly less sensitive to MD at the tail of the critical period, and are completely insensitive to MD as adults. Two-way ANOVA on CBIs of all groups (P26, P35, P42, adult; both genotypes) showed a significant effect of age (p = 0.004) but not of genotype, and no significant interaction between age and genotype.