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Abstract
Patients with Huntington’s disease exhibit memory and cognitive deficits many years before manifesting motor disturbances. Similarly, several studies have shown that deficits in long-term synaptic plasticity, a cellular basis of memory formation and storage, occur well before motor disturbances in the hippocampus of the transgenic mouse models of Huntington’s disease. The autosomal dominant inheritance pattern of Huntington’s disease suggests the importance of the mutant protein, huntingtin, in pathogenesis of Huntington’s disease, but wild type huntingtin also has been shown to be important for neuronal functions such as axonal transport. Yet, the role of wild type huntingtin in long-term synaptic plasticity has not been investigated in detail. We identified a huntingtin homolog in the marine snail Aplysia, and find that similar to the expression pattern in mammalian brain, huntingtin is widely expressed in neurons and glial cells. Importantly the expression of mRNAs of huntingtin is upregulated by repeated applications of serotonin, a modulatory transmitter released during learning in Aplysia. Furthermore, we find that huntingtin expression levels are critical, not only in presynaptic sensory neurons, but also in the postsynaptic motor neurons for serotonin-induced long-term facilitation at the sensory-to-motor neuron synapse of the Aplysia gill-withdrawal reflex. These results suggest a key role for huntingtin in long-term memory storage.
Highlights
Huntington’s disease (HD) is caused by a mutation that expands the number of trinucleotides CAG repeats in a gene leading to an expansion of polyglutamine stretch in huntingtin, the encoded protein (The Huntington’s Disease Collaborative Research Group, 1993)
Aplysia homolog of huntingtin (ApHTT) has a high degree of sequence conservation in the region of HEAT (Huntingtin, elongation factor 3, regulatory A submit of protein phosphatase 2a and TOR1) repeats, which cluster in three domains in the N-terminal half of human huntingtin, and is thought to be involved in protein-protein interactions [40]
Having established that antisense oligonucleotides are able to knock down ApHTT mRNA levels in sensory neurons, we examined whether the down regulation of ApHTT mRNA by antisense oligonucleotides in the presynaptic sensory neurons affects basal synaptic transmission in the sensory-motor neuron synapse by measuring excitatory postsynaptic potentials (EPSPs) at 24 hours after oligonucleotides injection (50 ng/ml) to the presynaptic sensory neurons. (Figure 5D; % change in EPSP amplitude: no injection 210.066.0, n = 7; antisense oligo alone 2 3.469.6, n = 7; sense oligo alone 210.265.7, n = 8)
Summary
Huntington’s disease (HD) is caused by a mutation that expands the number of trinucleotides CAG repeats in a gene leading to an expansion of polyglutamine stretch in huntingtin, the encoded protein (The Huntington’s Disease Collaborative Research Group, 1993). In HD, early cognitive deficits occur many years prior to overt motor deficits [2], a finding observed in a transgenic mouse model of HD [3]. Synaptic dysfunction is noted many years before the neuronal cell loss characteristic of neurodegenerative diseases [4,5]. Transgenic mice containing mutant huntingtin exhibit reduced long-term potentiation (LTP) as well as an abnormal development of NMDA-dependent long-term depression (LTD) in the hippocampus [6,7,8,9]
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