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SummaryApolipoprotein E receptor 2 (Apoer2), a member of the LDL receptor gene family, and its ligand Reelin control neuronal migration during brain development. Apoer2 is also essential for induction of long-term potentiation (LTP) in the adult brain. Here we show that Apoer2 is present in the postsynaptic densities of excitatory synapses where it forms a functional complex with NMDA receptors. Reelin signaling through Apoer2 markedly enhances LTP through a mechanism that requires the presence of amino acids encoded by an exon in the intracellular domain of Apoer2. This exon is alternatively spliced in an activity-dependent manner and is required for Reelin-induced tyrosine phosphorylation of NMDA receptor subunits. Mice constitutively lacking the exon perform poorly in learning and memory tasks. Thus, alternative splicing of Apoer2, a novel component of the NMDA receptor complex, controls the modulation of NMDA receptor activity, synaptic neurotransmission, and memory by Reelin.

6q23.3 (AHI1*) Jouberin; interacts with b-catenin in cilia Joubert syndrome. (Reduced brain and body size. Cerebellar, retinal, and kidney defects. Most die by P10. Neuron-specific loss leads to depressive-like phenotypes.)7q35-q36.1 (CNTNAP2*)Caspr2, a neurexin family member; clusters voltage-gated K+ channels Recessive EPI syndrome, ASD, ADHD, TS, OCD. (Neuronal migration defects. Reduced GABAergic neurons and decreased cortical synchrony. Seizures. Deficits in social, repetitive behaviors, and USV.) 9q34.13 (TSC1) Hamartin, a growth inhibitory protein that negatively regulates the mTOR pathwayTuberous Sclerosis type I. (Liver and neural tube defects. Die by E12. Abnormal kidney and liver growth in heterozygotes. Variable brain structure, function and behavior abnormalities in conditional mutants. Die at various postnatal ages. Neuron-specific loss causes abnormal spine morphology and cortical excitability. Loss of LTD.)10q23.31 (PTEN) Protein tyrosine phosphatase; negatively regulates the mTOR pathwayCowden disease. (Placenta and germ cell defects. Die by E9.5. Neuron-specific loss alters synaptic physiology. Heterozygotes have prostate, skin and colon defects, and spontaneous tumors. Macrocephaly, neuronal hypertrophy, abnormal social interaction, and increased survival in conditional mutants.)11q13.4 (DHCR7) Final enzyme in cholesterol biosynthetic pathwaySmith-Lemli-Opitz syndrome. (Craniofacial and lung abnormalities. Die by P1. Abnormal cholesterol regulation and enlarged bladders. Hypomorphic mutants are viable and fertile. Compound mutants have fused toes, enlarged ventricles, and 25% embryonic lethality.) 12p13.33 (CACNA1C)a-1 subunit of a voltage-dependent Ca2+ channelTimothy syndrome. (Die embryonically. Impaired pancreatic function. Motor defects and antidepressant-like behavior in heterozygotes; anxiety-like deficits in females. Neuron-specific loss, impaired cognition and LTP.) 15q11.2 (UBE3A) Ubiquitination ligase; targets protein degradation systemAngelman syndrome. (Small brain, seizure susceptibility, motor and learning deficits. Reduced spine density and impaired LTP. Impaired synapse maturation and plasticity.) 16p13.3 (TSC2) Tuberin; which negatively regulates the mTOR pathwayTuberous Sclerosis type II. (Heart, neural tube, and motor defects. Purkinje cell death. Die by E12. Various tumors and axon guidance defects in heterozygotes. Dominant-negative mutant has enhanced anxiety-like behaviors; motor, learning, social behavior deficits.) 17q11.2 (NF1) Neurofibromin; a GTPase activator and negative regulator of RAS signaling Neurofibromatosis. (Macrocephaly, small eyes, and heart defects. Delayed organ development. Embryonic lethal. Increased astrocytes and tumor susceptibility. LTP and learning and memory deficits in heterozygotes.) Xp21.2 (DMD) Dystrophin; cytoskeletal protein bridging ECMDuchenne muscular dystrophy. (Muscle and heart defects in hemizygous males and homozygous females. Reduced fertility. Abnormal retinal electrophysiology and synapse organization, density, and maturation.)Xp21.3 (ARX) Aristaless-related homeobox protein TFLIS, XLID, EPI, ASD. (Hemizygous males die perinatally. Decreased inhibitory synaptic transmission. Males hemizygous for point mutations or triple repeat expansions have seizures. Defects in behavior and GABAergic neuron generation and migration.)Xq27.3 (FMR1) Fragile X mental retardation protein; an RNA-binding protein that traffics mRNA Fragile X syndrome. (Seizures. Enlarged testes in males. Learning and social behavior defects. Dendritic spine abnormalities. Enhanced LTD and impaired LTP. Altered cortical drive and E/I neuronal cortical networks.) Xq28 (MECP2) MeCP2; involved in transcriptional regulation and chromatin organizationRett syndrome. (Brain, breathing, and motor defects in hemizygous males. Mild cognitive and anxiety-like phenotypes in heterozygous females. Various conditional loss and postnatal reduction mimic null phenotypes in adult hemizygous males. Impaired excitatory synapses and spine morphology. Increased neuronal connectivity.)