Hippocampal LTD, Cognitive Dysfunction, and Cognition-Enhancing Drugs
Evidence supports the idea that LTD may contribute to cognitive dysfunction. For example, soluble ► amyloid-beta protein (Aß) extracted from the brains of ► Alzheimer's disease patients enhances hippocampal mGluR-dependent LTD and disrupts the memory of learned behavior in rats (Shankar et al. 2008). Mouse models of ► Huntington's disease, a neurological disorder involving cognitive dysfunction, exhibit impairments in CA1 hippocampal LTD as well as behavioral deficits in hippocampal ► spatial learning tasks (e.g., Murphy et al. 2000). NMDAR-dependent hippocampal LTD is both necessary and sufficient to cause an acute ► stress-induced impairment of ► spatial memory retrieval and may be involved in mediating some of the cognitive deficits that occur in disorders whose symptoms are aggravated by stress (reviewed by Massey and Bashir 2007). Taken together, these data suggest an underlying role for the mechanisms of hippocampal LTD in some aspects of cognitive dysfunction associated with specific neurological disorders.
Mechanisms underlying hippocampal LTD serve as possible drug targets for the treatment of cognitive dysfunction. For example, 17beta-estradiol ameliorates cognitive and memory dysfunction in postmenopausal women in addition to minimally suppressing hippocam-pal LTD in adult rats, suggesting that estrogen may act to improve memory by suppressing forgetfulness via a synaptic mechanism such as LTD (Vouimba et al. 2000). The NMDAR co-agonist d-serine enhances ► NR2B-dependent hippocampal LTD and reversal learning in the ► Morris water maze, supporting a role for NMDAR-dependent LTD in spatial learning, and highlighting molecular components of the LTD mechanism as targets for cognition-enhancing drugs.
VTA LTD is blocked by dopamine D2 (but not D1) receptor agonists (reviewed by Wolf et al. 2004), and therefore may be targeted by drugs of abuse that cause an increase in extracellular dopamine levels in the VTA. This has been shown for ► amphetamine, which blocks and reverses the somatodendritic ► dopamine transporter, thus causing release of dopamine within the VTA. one might expect that D2 receptor antagonists, such as many of the anti-psychotic drugs used to treat ► schizophrenia, could potentially enhance VTA LTD. However, comprehensive testing of the antipsychotic drugs used in clinical practice against VTA LTD has not been carried out.
If VTA LTD acts as a "brake" on the excitability of dopaminergic neurons (Kauer 2004), inhibiting LTD may provide a window of opportunity for synaptic strengthening. This ► synaptic plasticity would be associated with the salient event that caused elevated levels of extracellular dopamine in the VTA - for example, acquisition of novel reward information, or the presence of a drug of abuse. Such associations may contribute to the learning of procedural information with respect to drug-seeking and drug-taking behaviors that are, one might argue, mal-adaptive forms of memory. Conversely, induction of VTA mGluR-LTD reverses the ► cocaine-induced strengthening of glutamatergic synapses in dopaminergic neurons, and is a putative mechanism for reversing the neuronal plasticity induced by cocaine (Bellone and Luscher 2006).
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