BDNF Val66Met knock-in mice have stress-like deficits in dendritic morphology and excitatory synaptic responses in layer V pyramidal cells of medial prefrontal cortex.
R.-J. LIU; F. S. LEE; R. S. DUMAN; G. K. AGHAJANIAN
Society for Neuroscience. 2009.
The Val66Met allele for BDNF is carried by ~30% of the general population and has been associated with major depression and bipolar disorder. Creation of the Val66Met knock-in mouse offers an opportunity to explore the implications of this human polymorphism in an animal model. Our previous studies have shown that BDNF deficient heterozygous knockout (BDNF+/-) mice have constitutive atrophy of distal apical dendrites and deficits in apically-targeted excitatory synaptic responses in layer V pyramidal cells of medial prefrontal cortex (mPFC); the decrements in synaptic responses are associated with reductions in the density of distal apical dendritic spines. These changes are strikingly similar to deficits seen in wild type mice exposed to repeated restraint stress, which is known to down regulate BDNF. Since the Met allele has been shown to impair trafficking of BDNF, we hypothesized that mice with the Met allele would also produce stress-like changes in morphology and function in layer V mPFC pyramidal cells. Whole cell recordings of 5-HT- and hypocretin-induced EPSCs were made from layer V pyramidal neurons in brain slices; the pipette solution contained Neurobiotin to label cells. Subsequent to recordings, slices were fixed in formalin and stained with streptavidin conjugated to Alexa 594 and then examined by 2-photon laser scanning (Liu and Aghajanian, 20081). Results show that Val/Met and Met/Met mice have constitutive atrophy of distal apical dendrites and decrements in apically-targeted excitatory synaptic responses in layer V mPFC pyramidal cells. These preexisting changes are similar to deficits seen in BDNF+/- as well as wild type mice exposed to repeated restraint stress. However, in contrast to stressed or BDNF+/- mice, Met allele mice also showed basilar dendritic atrophy; these changes were more pronounced in the Met/Met mice. Nevertheless, BDNF+/- and Met mice are alike in that the changes are present even without a deliberate stress protocol. Preliminary studies in wild type mice indicate that changes induced by repeated mild restraint stress show a gradual reversal starting within a week after the cessation of stress. Since vulnerability to depression or bipolar disease in individuals with the Met polymorphism is aggravated by early or recurrent stress, it is possible a deficit in BDNF function renders them unable to recover from the effects of stressful life experiences. Future studies will be aimed at seeing whether wild type mice would fail to recover from the effects of repeated stress if BDNF signaling were experimentally impaired.