Autism spectrum disorders (ASDs) are characterized by impairments in social behaviors that are sometimes coupled to specialized cognitive abilities. A small percentage of ASD patients carry mutations in genes encoding neuroligins, which are postsynaptic cell-adhesion molecules. We introduced one of these mutations into mice: the Arg451-->Cys451 (R451C) substitution in neuroligin-3. R451C mutant mice showed impaired social interactions but enhanced spatial learning abilities. Unexpectedly, these behavioral changes were accompanied by an increase in inhibitory synaptic transmission with no apparent effect on excitatory synapses. Deletion of neuroligin-3, in contrast, did not cause such changes, indicating that the R451C substitution represents a gain-of-function mutation. These data suggest that increased inhibitory synaptic transmission may contribute to human ASDs and that the R451C knockin mice may be a useful model for studying autism-related behaviors.

CNS deletion of Pten in the mouse has revealed its roles in controlling cell size and number, thus providing compelling etiology for macrocephaly and Lhermitte-Duclos disease. PTEN mutations in individuals with autism spectrum disorders (ASD) have also been reported, although a causal link between PTEN and ASD remains unclear. In the present study, we deleted Pten in limited differentiated neuronal populations in the cerebral cortex and hippocampus of mice. Resulting mutant mice showed abnormal social interaction and exaggerated responses to sensory stimuli. We observed macrocephaly and neuronal hypertrophy, including hypertrophic and ectopic dendrites and axonal tracts with increased synapses. This abnormal morphology was associated with activation of the Akt/mTor/S6k pathway and inactivation of Gsk3beta. Thus, our data suggest that abnormal activation of the PI3K/AKT pathway in specific neuronal populations can underlie macrocephaly and behavioral abnormalities reminiscent of certain features of human ASD.

Brain-derived neurotrophic factor (BDNF) regulates neuronal development and function. However, it has been difficult to discern its role in the adult brain in influencing complex behavior. Here, we use a recently developed inducible knockout system to show that deleting BDNF in broad forebrain regions of adult mice impairs hippocampal-dependent learning and long-term potentiation. We use the inducible nature of this system to show that the loss of BDNF during earlier stages of development causes hyperactivity and more pronounced hippocampal-dependent learning deficits. We also demonstrate that the loss of forebrain BDNF attenuates the actions of desipramine, an antidepressant, in the forced swim test, suggesting the involvement of BDNF in antidepressant efficacy. These results establish roles for BDNF in the adult, and demonstrate the strength of this inducible knockout system in studying gene function in the adult brain.B rain-derived neurotrophic factor (BDNF) is a member of the neurotrophin family of growth factors (1, 2). It is widely expressed in the mammalian brain (3) and regulates many aspects of neuronal function (4-8). However, a role for BDNF in regulating complex behavior has been difficult to assess, because of the lack of specific pharmacological agents and the early postnatal lethality of BDNF null (Ϫ͞Ϫ) mice (9). Studies examining heterozygous BDNF (ϩ͞Ϫ) mice, which display roughly half the normal levels of BDNF in brain, have reported increased feeding behavior, obesity, hyperactivity, and aggressiveness (10-12). However, these alterations may arise from developmental abnormalities and complicate the interpretation of the role of BDNF in the adult brain.The recent generation of conditional BDNF knockout (KO) mice circumvents the problem of postnatal lethality and allows for some regional specificity of gene deletion. For example, conditional BDNF KO mice survive to adulthood and exhibit a range of deficits similar to those seen in the heterozygous null mice (13). However, such conditional KO mice still suffer from the fact that they delete a gene of interest during late-embryonic or early postnatal periods and thus do not preclude developmental abnormalities as the cause of behavioral impairments observed. This is of a particular concern in studying complex behavior because early developmental periods in humans are crucial for the manifestation of many complex neuropsychiatric illnesses. To truly investigate the influence of BDNF on complex behavior in adults, it is necessary to have a system in which BDNF is deleted in an inducible manner in specific brain regions. We have generated an inducible KO system in which BDNF can be deleted selectively in the brain of adult mice. Here we describe the phenotype of mice in which BDNF has been deleted in broad forebrain regions of adult mice. We use the inducibility of the system to examine the phenotype of mice in which BDNF has been deleted at earlier stages of development in the same brain regions. Our results demonstrate that the role of BDNF in the ...