To better understand learning mechanisms, one needs to study synaptic plasticity induced by behavioral training. Recently, it has been demonstrated that the cerebellum is involved in the consolidation of fear memory. Nevertheless, how the cerebellum contributes to emotional behavior is far from known. In cerebellar slices at 10 min and 24 hr following fear conditioning, we found a long-lasting potentiation of the synapse between parallel fibers and Purkinje cells in vermal lobules V-VI, but not in the climbing fiber synapses. The mechanism is postsynaptic, due to an increased AMPA response. In addition, in hotfoot mice with a primary deficiency of the parallel fiber to Purkinje cell synapse, cued (but not contextual) fear conditioning is affected. We propose that this synapse plays an important role in the learned fear and that its long-term potentiation may represent a contribution to the neural substrate of fear memory.
GABAergic synapses are crucial for brain function, but the mechanisms underlying inhibitory synaptogenesis are unclear. Here, we show that postnatal Purkinje cells (PCs) of GABAA␣1 knockout (KO) mice express transiently the ␣3 subunit, leading to the assembly of functional GABAA receptors and initial normal formation of inhibitory synapses, that are retained until adulthood. Subsequently, down-regulation of the ␣3 subunit causes a complete loss of GABAergic postsynaptic currents, resulting in a decreased rate of inhibitory synaptogenesis and formation of mismatched synapses between GABAergic axons and PC spines. Notably, the postsynaptic adhesion molecule neuroligin-2 (NL2) is correctly targeted to inhibitory synapses lacking GABAA receptors and the scaffold molecule gephyrin, but is absent from mismatched synapses, despite innervation by GABAergic axons. Our data indicate that GABAA receptors are dispensable for synapse formation and maintenance and for targeting NL2 to inhibitory synapses. However, GABAergic signaling appears to be crucial for activity-dependent regulation of synapse density during neuronal maturation.gephyrin ͉ Purkinje cell ͉ synaptogenesis T he identification of the factors that are critical for the assembly, maturation, and stabilization of synaptic connections remains a central puzzle in developmental neuroscience. Studies on cultured neurons have been invaluable for uncovering the molecular mechanisms of synaptogenesis (1, 2). Unfortunately, such studies can be influenced by varying experimental conditions, and their results often have not been replicated by in vivo analyses of gene knockout (KO) mice (3). As an alternative approach, gene deletion techniques allow investigating the in vivo function of genes that are believed to be critical for synapse formation (4-8). However, the premature death of newborn mutant mice has often prevented long-term analyses of synapse maturation and function. In the present study, we took advantage of a KO model that survives up to adulthood without a major phenotype, despite extensive loss of GABA-mediated function in specific populations of neurons.Specifically, we investigated the in vivo effects of a selective silencing of GABAergic transmission on the formation and longterm stability of GABAergic synapses, which provide the major inhibitory control over neuronal activity in the brain (9). By analogy to glutamatergic synapses, assembly of GABAergic synapses is believed to involve selective trans-synaptic interactions between adhesion molecules and cytosolic interactions with scaffolding proteins (2). Neuroligin-2 (NL2) is a postsynaptic adhesion molecule that localizes at GABAergic synapses and triggers synapse formation by interacting with presynaptic neurexins (10, 11). NL2 belongs to a family of related proteins also comprising NL1, NL3, and NL4 (12). Importantly, NL1 is targeted to glutamatergic synapses (13,14), suggesting that different NLs may play an important role in specifying distinct types of synapse and in determining a balance between n...
In addition to coordinating movement, the cerebellum participates in motor learning, emotional behavior, and fear memory. Fear learning is reflected in a change of autonomic and somatic responses, such as heart rate and freezing, elicited by a neutral stimulus that has been previously paired with a painful one. Manipulation of the vermis affects these responses, and its reversible inactivation during the consolidation period impairs fear memory. The neural correlate of cerebellar involvement in fear consolidation is provided by a behaviorally induced long-term increase of synaptic efficacy between parallel fibers and a Purkinje cell. Similar synaptic changes after fear conditioning are well documented in the amygdala and hippocampus, providing a link between emotional experiences and changes in neural activity. In addition, in hotfoot mice, with a primary deficiency of parallel fiber to Purkinje cell synapse, short- and long-term fear memories are affected. All these data support the idea that the cerebellum participates in fear learning. The functional interconnection of the vermis with hypothalamus, amygdala, and hippocampus suggests a more complex role of the cerebellum as part of an integrated network regulating emotional behavior.
Fear conditioning involves learning that a previously neutral stimulus (CS) predicts an aversive unconditioned stimulus (US). Lesions of the cerebellar vermis may affect fear memory without altering baseline motor/autonomic responses to the frightening stimuli. Reversible inactivation of the vermis during the consolidation period impairs retention of fear memory. In patients with medial cerebellar lesions conditioned bradycardia is impaired. In humans, cerebellar areas around the vermis are activated during mental recall of emotional personal episodes, if a loved partner receives a pain stimulus, and during learning of a CS-US association. Moreover, patients with cerebellar stroke may fail to show overt emotional changes. In such patients, however, the activity of several areas, including ventromedial prefrontal cortex, anterior cingulate, pulvinar and insular cortex, is significantly increased relative to healthy subjects when exposed to frightening stimuli. Therefore, other structures may serve to maintain fear response after cerebellar damage. These data indicate that the vermis is involved in the formation of fear memory traces. We suggest that the vermis is not only involved in regulating the autonomic/motor responses, but that it also participates in forming new CS-US associations thus eliciting appropriate responses to new stimuli or situations. In other words, the cerebellum may translate an emotional state elaborated elsewhere into autonomic and motor responses.
Despite the widespread distribution of inhibitory synapses throughout the central nervous system, plasticity of inhibitory synapses related to associative learning has never been reported. In the cerebellum, the neural correlate of fear memory is provided by a long-term potentiation (LTP) of the excitatory synapse between the parallel fibers (PFs) and the Purkinje cell (PC). In this article, we provide evidence that inhibitory synapses in the cerebellar cortex also are affected by fear conditioning. Whole-cell patch-clamp recordings of spontaneous and miniature GABAergic events onto the PC show that the frequency but not the amplitude of these events is significantly greater up to 24 h after the conditioning. Adequate levels of excitation and inhibition are required to maintain the temporal fidelity of a neuronal network. Such fidelity can be evaluated by determining the time window for multiple input coincidence detection. We found that, after fear learning, PCs are able to integrate excitatory inputs with greater probability within short delays, but the width of the whole window is unchanged. Therefore, excitatory LTP provides a more effective detection, and inhibitory potentiation serves to maintain the time resolution of the system. cerebellum ͉ associative learning ͉ GABA inhibition ͉ Purkinje cells ͉ fear M ost investigations of long-term changes in synaptic transmission related to learning and memory processes have been carried out on excitatory synapses by using electrical stimulation to induce long-term potentiation (LTP). Several examples of behaviorally induced LTP have been described in the hippocampus (1-4), cerebellum (5), and amygdala (6, 7) after associative learning. Recently, long-term changes induced by electrical stimulation also have been observed at inhibitory synapses within several brain areas, including the cerebellum (8-10), hippocampus (11), brainstem (12), and lateral amygdala (13,14). In addition, long-lasting plasticity of inhibitory synapses has been reported in vivo that mediates desensitization of the goldfish escape response (15). Inhibitory plasticity also can be induced in the developing Xenopus retinotectal system as a result of sensory experiences such as repetitive light stimuli (16). The existence of GABAergic synaptic plasticity induced in vivo by associative learning and its physiological role remains to be elucidated.Integration of excitatory and inhibitory signals is a basic attribute of neuronal communication. A common feature of central neuronal circuits is that excitatory responses are truncated by incoming inhibition mediated by GABAergic interneurons (feed-forward inhibition, or FFI). Recent studies, both in the hippocampus and cerebellum, have shown that FFI plays a fundamental role in shaping the time window in which excitatory inputs can summate to reach the threshold for spike generation (17, 18). In fact, this time window is an indication of the temporal resolution for neuronal integration. Recently, it has been shown that the time window for multiple input c...
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