Many central neurons possess large acid-activated currents, yet their molecular identity is unknown. We found that eliminating the acid sensing ion channel (ASIC) abolished H(+)-gated currents in hippocampal neurons. Neuronal H(+)-gated currents and transient acidification are proposed to play a role in synaptic transmission. Investigating this possibility, we found ASIC in hippocampus, in synaptosomes, and in dendrites localized at synapses. Moreover, loss of ASIC impaired hippocampal long-term potentiation. ASIC null mice had reduced excitatory postsynaptic potentials and NMDA receptor activation during high-frequency stimulation. Consistent with these findings, null mice displayed defective spatial learning and eyeblink conditioning. These results identify ASIC as a key component of acid-activated currents and implicate these currents in processes underlying synaptic plasticity, learning, and memory.

The idea that memory is encoded by means of synaptic growth is not new. However, this idea has been difficult to demonstrate in the mammalian brain because of both the complexity of mammalian behavior and the neural circuitry by which it is supported. Here we examine how eyeblink classical conditioning affects synapse number within the cerebellum; the brain region essential for long-term retention of the conditioned response. Results showed eyeblink-conditioned rats to have significantly more synapses per neuron within the cerebellar interpositus nucleus than both explicitly unpaired and untrained controls. Further analysis showed that the increase was caused by the addition of excitatory rather than inhibitory synapses. Thus, development of the conditioned eyeblink response is associated with a strengthening of inputs from precerebellar nuclei rather than from cerebellar cortex. These results demonstrate that the modifications of specific neural pathways by means of synaptogenesis contributes to formation of a specific memory within the mammalian brain.For every act of memory, every exercise of bodily aptitude, every habit, recollection, train of ideas, there is a specific neural grouping, or co-ordination, of sensations and movement, by virtue of specific growths in cell junctions (1).T he neural circuits critical for the acquisition and performance of the conditioned eyeblink response are localized to the cerebellum (2). Information regarding the unconditioned stimulus (US) and conditioned stimulus (CS) converge within both the cerebellar cortex and the interpositus nucleus. CS information is relayed via ponto-cerebellar projections, whereas US information is relayed via the olivo-cerebellar pathway (2, 3). Although the cerebellar cortex is involved in modulating some aspects of the conditioned response (CR) (4, 5), the interpositus nucleus is the critical brain structure supporting long-term retention of the CR (2, 6, 7). Neuronal activity within the interpositus nucleus is highly correlated with development of the CR (5, 7), and inactivation of the interpositus prevents both CR acquisition and performance (8).Although the locus of the memory trace is clear, the cellular mechanisms underlying the formation of the CS͞US association are poorly understood. Several mechanisms have been proposed, including increases in the intrinsic excitability of interpositus neurons and reduced inhibition via depression of Purkinje cell activity (9). The fact that inhibition of specific synaptic enzymes (10) and neurotransmitter receptors (11) within the interpositus nucleus impair learning suggests that changes in synaptic function are involved. Transient changes in enzyme or receptor activity, however, would seem incapable of supporting the long-term encoding of the CS͞US association. Recent work has shown that microinjections of a protein synthesis inhibitor into the interpositus nucleus impairs the acquisition but not the expression of the CR (12). This finding suggests that strengthening of the CS pathway may involve more...

The current study examined the effects of globally depleting Purkinje cells in the cerebellar cortex with the immunotoxin OX7-saporin on acquisition and extinction of delay eyeblink conditioning in rats. Rats were given OX7-saporin or saline 2 wk before the start of eyeblink conditioning. The rats that reached a performance criterion of two consecutive days with 80% or greater conditioned responses were given 5 d of extinction training followed by 2 d of reacquisition training. Rats that received infusions of OX7-saporin had 77.2%-97.9% Purkinje cell loss and exhibited impaired acquisition and extinction. The amount of Purkinje cell loss was correlated with the magnitude of the acquisition and extinction impairments. The highest correlations between Purkinje cell number and the rate of acquisition were in lobule HVI and the anterior lobe. The highest negative correlation between Purkinje cell number and the percentage of conditioned responses during extinction was in the anterior lobe. The results indicate that cerebellar Purkinje cells, particularly in the anterior lobe and lobule HVI, play significant roles in acquisition and extinction of eyeblink conditioning.Cerebellar learning is critical for making adaptive adjustments to movements. An early model of cerebellar learning proposed by Albus (1971) suggests that learning-specific changes in synaptic function occur exclusively in the cerebellar cortex. Empirical evidence supporting learning-specific changes in cerebellar cortex initially came from neurophysiological analyses of arm movements and adaptation of the vestibular ocular reflex (Ito 1972;Gilbert and Thach 1977;Ito and Kano 1982). Evidence subsequently emerged that indicated a critical role for learning-specific plasticity in the cerebellar and vestibular nuclei (Miles and Lisberger 1981; McCormick and Thompson 1984a,b). The most prevalent view currently is that learning-specific plasticity occurs in the cerebellar cortex and deep nuclei (Mauk and Donegan 1997;Steinmetz 2000;Christian and Thompson 2003). The computational model of Mauk and colleagues further specifies that plasticity in the cerebellar cortex is critical for initial acquisition and timing of conditioned responses, whereas plasticity in the interpositus nucleus is necessary for long-term storage of a basic (not precisely timed) conditioned response (CR) (Medina et al. 2001;Ohyama and Mauk 2001).The precise role of the cerebellar cortex in eyeblink conditioning has been difficult to establish, due primarily to discrepant findings between laboratories. Some laboratories found that cortical lesions abolished eyeblink CRs, while others found recoverable deficits, depending on lesion size, location, and amount of pre-lesion training (McCormick and Thompson 1984a;Yeo et al. 1985;Lavond et al. 1987;Lavond and Steinmetz 1989;Yeo and Hardiman 1992;Harvey et al. 1993;Perrett et al. 1993;Woodruff-Pak et al. 1993). Moreover, Yeo and colleagues demonstrated that reversible inactivation of cortical activity in HVI and the anterior lobe abolished CRs,...

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