Brain-derived neurotrophic factor (BDNF) has trophic effects on serotonergic (5-HT) neurons in the central nervous system. However, the role of endogenous BDNF in the development and function of these neurons has not been established in vivo because of the early postnatal lethality of BDNF null mice. In the present study, we use heterozygous BDNF ؉͞؊ mice that have a normal life span and show that these animals develop enhanced intermale aggressiveness and hyperphagia accompanied by significant weight gain in early adulthood; these behavioral abnormalities are known to correlate with 5-HT dysfunction. Forebrain 5-HT levels and fiber density in BDNF ؉͞؊ mice are normal at an early age but undergo premature age-associated decrements. However, young adult BDNF ؉͞؊ mice show a blunted c-fos induction by the specific serotonin releaser-uptake inhibitor dexfenfluramine and alterations in the expression of several 5-HT receptors in the cortex, hippocampus, and hypothalamus. The heightened aggressiveness can be ameliorated by the selective serotonin reuptake inhibitor fluoxetine. Our results indicate that endogenous BDNF is critical for the normal development and function of central 5-HT neurons and for the elaboration of behaviors that depend on these nerve cells. Therefore, BDNF ؉͞؊ mice may provide a useful model to study human psychiatric disorders attributed to dysfunction of serotonergic neurons.T he neurotrophin brain-derived neurotrophic factor (BDNF) influences the phenotype, structural plasticity, and perhaps survival of central serotonergic (5-HT) neurons (1-3). Disturbances in brain 5-HT systems have been implicated in psychiatric syndromes characterized by behavioral dyscontrol, such as obsessive-compulsive disorder, bulimia, chronic impulsivity͞ aggression, and violent suicide (4-7). Many of these psychiatric syndromes are being treated with compounds that augment 5-HT neurotransmission in the brain, including selective serotonin reuptake inhibitors and 5-HT receptor agonists (8, 9). Pharmacological studies indicate that exogenously administered BDNF has trophic effects on 5-HT neurons. For example, BDNF administration increases 5-HT metabolism in the brain (3) and stimulates the local sprouting of 5-HT fibers in the cerebral cortex and spinal cord (2, 10, 11). The enhancement of 5-HT neurotransmission by exogenous BDNF potentiates several behaviors regulated by serotonin (12, 13) and has antidepressantlike effects in animal models of depression (14). However, the role of endogenous BDNF in the normal development and function of 5-HT neurons has not been determined.A major obstacle in elucidating the role of endogenous BDNF has been the early postnatal lethality of BDNF Ϫ͞Ϫ mice. However, recent studies confirmed the presence of several nonlethal, functional defects within the peripheral and central nervous systems of heterozygous animals with one functional BDNF allele, suggesting that BDNF is haploinsufficient. For example, targeted mutation of the BDNF locus causes deficits in hippocampal synaptic funct...

Cerebellar LTD requires activation of PKC and is expressed, at least in part, as postsynaptic AMPA receptor internalization. Recently, it was shown that AMPA receptor internalization requires clathrin-mediated endocytosis and depends upon the carboxy-terminal region of GluR2/3. Phosphorylation of Ser-880 in this region by PKC differentially regulates the binding of the PDZ domain-containing proteins GRIP/ABP and PICK1. Peptides, corresponding to the phosphorylated and dephosphorylated GluR2 carboxy-terminal PDZ binding motif, were perfused in cerebellar Purkinje cells grown in culture. Both the dephospho form (which blocks binding of GRIP/ABP and PICK1) and the phospho form (which selectively blocks PICK1) attenuated LTD induction by glutamate/depolarization pairing, as did antibodies directed against the PDZ domain of PICK1. These findings indicate that expression of cerebellar LTD requires PKC-regulated interactions between the carboxy-terminal of GluR2/3 and PDZ domain-containing proteins.