Mutations in the ␣-synuclein (␣SYN) gene are associated with rare cases of familial Parkinson's disease, and ␣SYN is a major component of Lewy bodies and Lewy neurites. Here we have investigated the localization of wild-type and mutant [A30P]␣SYN as well as ␤SYN at the cellular and subcellular level. Our direct comparative study demonstrates extensive synaptic colocalization of ␣SYN and ␤SYN in human and mouse brain. In a sucrose gradient equilibrium centrifugation assay, a portion of ␤SYN floated into lower density fractions, which also contained the synaptic vesicle marker synaptophysin. Likewise, wild-type and [A30P]␣SYN were found in floating fractions. Subcellular fractionation of mouse brain revealed that both ␣SYN and ␤SYN were present in synaptosomes. In contrast to synaptophysin, ␤SYN and ␣SYN were recovered from the soluble fraction upon lysis of the synaptosomes. (Surguchov et al., 1999). The central domain of ␣SYN had been originally identified as the non-amyloid ␤-protein component (NAC) of Alzheimer's disease plaques (Uéda et al., 1993). Full-length ␣SYN has been subsequently found in Lewy bodies (LBs), pale bodies, and Lewy neurites of patients with Parkinson's disease (PD) and dementia with LBs, as well as in cytoplasmic inclusions characteristic for multiple system atrophy (Spillantini et al., 1997;Arima et al., 1998;Baba et al., 1998;Spillantini et al., 1998;Takeda et al., 1998a;Tu et al., 1998;Wakabayashi et al., 1998;Culvenor et al., 1999). LBs were ␣SYN-positive in LB variant of Alzheimer's disease, familial Alzheimer's disease, and Down's syndrome (Lippa et al., 1998(Lippa et al., , 1999Takeda et al., 1998b), as well as in neurodegeneration with brain iron accumulation type 1 (formerly known as HallervordenSpatz disease) (Arawaka et al., 1998;Wakabayashi et al., 1999).Two missense mutations in the ␣SYN gene have been linked to familial PD (Polymeropoulos et al., 1997;Krüger et al., 1998). Both mutations accelerated the intrinsic property of ␣SYN to selfaggregate into fibrils that were morphologically similar to those isolated from LBs (Conway et al., 1998;Giasson et al., 1999;Narhi et al., 1999). Therefore, similar to most of the mutations associated with other familial forms of neurodegenerative disorders, ␣SYN mutations lead to the abnormal generation of an amyloidogenic variant, which is deposited in the disease-specific lesion (Hardy and Gwinn-Hardy, 1998;Lansbury, 1999;Selkoe, 1999).The physiological function of synucleins is unknown. Targeted disruption of the ␣SYN gene in mice caused a subtle perturbation in dopaminergic neurotransmission (Abeliovich et al., 2000). The identification of ␣SYN binding proteins has pointed to potential roles in signal transduction, perhaps in the context of axonal transport (Jenco et al., 1998;Engelender et al., 1999;Jensen et al., 1999;Ostrerova et al., 1999). Another link to signal transduction events may be indicated by the fact that both ␣SYN and ␤SYN are phosphorylated Okochi et al., 2000).Previous immunohistochemical studies suggested an enrichme...

GABA(B) (gamma-aminobutyric acid type B) receptors are important for keeping neuronal excitability under control. Cloned GABA(B) receptors do not show the expected pharmacological diversity of native receptors and it is unknown whether they contribute to pre- as well as postsynaptic functions. Here, we demonstrate that Balb/c mice lacking the GABA(B(1)) subunit are viable, exhibit spontaneous seizures, hyperalgesia, hyperlocomotor activity, and memory impairment. Upon GABA(B) agonist application, null mutant mice show neither the typical muscle relaxation, hypothermia, or delta EEG waves. These behavioral findings are paralleled by a loss of all biochemical and electrophysiological GABA(B) responses in null mutant mice. This demonstrates that GABA(B(1)) is an essential component of pre- and postsynaptic GABA(B) receptors and casts doubt on the existence of proposed receptor subtypes.

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To investigate the role of the myelin-associated protein Nogo-A on axon sprouting and regeneration in the adult central nervous system (CNS), we generated Nogo-A-deficient mice. Nogo-A knockout (KO) mice were viable, fertile, and not obviously afflicted by major developmental or neurological disturbances. The shorter splice form Nogo-B was strongly upregulated in the CNS. The inhibitory effect of spinal cord extract for growing neurites was decreased in the KO mice. Two weeks following adult dorsal hemisection of the thoracic spinal cord, Nogo-A KO mice displayed more corticospinal tract (CST) fibers growing toward and into the lesion compared to their wild-type littermates. CST fibers caudal to the lesion-regenerating and/or sprouting from spared intact fibers-were also found to be more frequent in Nogo-A-deficient animals.

Pavlovian fear conditioning, a simple form of associative learning, is thought to involve the induction of associative, NMDA receptor-dependent long-term potentiation (LTP) in the lateral amygdala. Using a combined genetic and electrophysiological approach, we show here that lack of a specific GABA(B) receptor subtype, GABA(B(1a,2)), unmasks a nonassociative, NMDA receptor-independent form of presynaptic LTP at cortico-amygdala afferents. Moreover, the level of presynaptic GABA(B(1a,2)) receptor activation, and hence the balance between associative and nonassociative forms of LTP, can be dynamically modulated by local inhibitory activity. At the behavioral level, genetic loss of GABA(B(1a)) results in a generalization of conditioned fear to nonconditioned stimuli. Our findings indicate that presynaptic inhibition through GABA(B(1a,2)) receptors serves as an activity-dependent constraint on the induction of homosynaptic plasticity, which may be important to prevent the generalization of conditioned fear.