Phosphorylation and dephosphorylation of cellular proteins by protein kinases and phosphatases represent important mechanisms for controlling major biological events. In the nervous system, protein phosphatases are contained in highly dynamic complexes localized within specialized subcellular compartments and they ensure timely dephosphorylation of multiple neuronal phosphoproteins. This modulates the responsiveness of individual synapses to neural activity and controls synaptic plasticity. These enzymes in turn play a key role in many forms of learning and memory, and their dysfunction contributes to cognitive deficits associated with aging and dementias or neurodegenerative diseases. Here, we review key modes of regulation of neuronal protein serine/threonine phosphatases and their contribution to disorders of learning and memory.

The actin-based dynamics of dendritic spines play a key role in synaptic plasticity, which underlies learning and memory. Although it is becoming increasingly clear that modulation of actin is critical for spine dynamics, the upstream molecular signals that regulate the formation and plasticity of spines are poorly understood. In non-neuronal cells, integrins are critical modulators of the actin cytoskeleton, but their function in the nervous system is not well characterized. Here we show that alpha5 integrin regulates spine morphogenesis and synapse formation in hippocampal neurons. Knockdown of alpha5 integrin expression using small interfering RNA decreased the number of dendritic protrusions, spines, and synapses. Expression of constitutively active or dominant negative alpha5 integrin also resulted in alterations in the number of dendritic protrusions, spines, and synapses. alpha5 integrin signaling regulates spine morphogenesis and synapse formation by a mechanism that is dependent on Src kinase, Rac, and the signaling adaptor GIT1. Alterations in the activity or localization of these molecules result in a significant decrease in the number of spines and synapses. Thus, our results point to a critical role for integrin signaling in regulating the formation of dendritic spines and synapses in hippocampal neurons.

Asymptomatic Huntington?s disease (HD) patients exhibit memory and cognition deficits that generally worsen with age. Similarly, long-term potentiation (LTP), a form of synaptic plasticity involved in memory encoding, is impaired in HD mouse models well before motor disturbances occur. The reasons why LTP deteriorates are unknown. Here we show that LTP is impaired in hippocampal slices from presymptomatic Hdh(Q92) and Hdh(Q111) knock-in mice, describe two factors contributing to this deficit, and establish that potentiation can be rescued with brain-derived neurotrophic factor (BDNF). Baseline physiological measures were unaffected by the HD mutation, but LTP induction and, to a greater degree, consolidation were both defective. The facilitation of burst responses that normally occurs during a theta stimulation train was reduced in HD knock-in mice, as was theta-induced actin polymerization in dendritic spines. The decrease in actin polymerization and deficits in LTP stabilization were reversed by BDNF, concentrations of which were substantially reduced in hippocampus of both Hdh(Q92) and Hdh(Q111) mice. These results suggest that the HD mutation discretely disrupts processes needed to both induce and stabilize LTP, with the latter effect likely arising from reduced BDNF expression. That BDNF rescues LTP in HD knock-in mice suggests the possibility of treating cognitive deficits in asymptomatic HD gene carriers by upregulating production of the neurotrophin.