In our previous studies, phosphorylation-dependent tau mislocalization to dendritic spines resulted in early cognitive and synaptic deficits. It is well known that amyloid beta (Aβ) oligomers cause synaptic dysfunction by inducing calcineurin-dependent AMPA receptor (AMPAR) internalization. However, it is unknown whether Aβ-induced synaptic deficits depend upon tau phosphorylation. It is also unknown whether changes in tau can cause calcineurin-dependent loss of AMPARs in synapses. Here, we show that tau mislocalizes to dendritic spines in cultured hippocampal neurons from APPSwe Alzheimer’s disease (AD)-transgenenic mice and in cultured rat hippocampal neurons treated with soluble Aβ oligomers. Interestingly, Aβ treatment also impairs synaptic function by decreasing the amplitude of miniature excitatory postsynaptic currents (mEPSCs). The above tau mislocalization and Aβ-induced synaptic impairment are both diminished by the expression of AP tau, indicating that these events require tau phosphorylation. The phosphatase activity of calcineurin is important for AMPAR internalization via dephosphorylation of GluA1 residue S845. The effects of Aβ oligomers on mEPSCs are blocked by the calcineurin inhibitor FK506. Aβ-induced loss of AMPARs is diminished in neurons from knock-in mice expressing S845A mutant GluA1 AMPA glutamate receptor subunits. This finding suggests that changes in phosphorylation state at S845 are involved in this pathogenic cascade. Furthermore, FK506 rescues deficits in surface AMPAR clustering on dendritic spines in neurons cultured from transgenic mice expressing P301L tau proteins. Together, our results support the role of tau and calcineurin as two intermediate signaling molecules between Aβ initiation and eventual synaptic dysfunction early in AD pathogenesis.

Drug-induced plasticity of excitatory synapses has been proposed to be the cellular mechanism underlying the aberrant learning associated with addiction. Exposure to various drugs of abuse causes both morphological plasticity of dendritic spines and functional plasticity of excitatory synaptic transmission. Chronic activation of -opioid receptors (MOR) in cultured hippocampal neurons causes two forms of synaptic plasticity: loss of dendritic spines and loss of synaptic ␣-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors. With use of live imaging, patch-clamp electrophysiology, and immunocytochemistry, the present study reveals that these two forms of synaptic plasticity are mediated by separate, but interactive, intracellular signaling cascades. The inhibition of Ca 2ϩ /calmodulin-dependent protein kinase II with 1-[N,O-bis(5-isoquinolinesulfonyl)-N-methyl-L-tyrosyl]-4-phenylpiperazine (KN-62) blocks MOR-mediated structural plasticity of dendritic spines, but not MOR-mediated cellular redistribution of GluR1 and GluR2 AMPA receptor subunits. In contrast, the inhibition of calcineurin with tacrolimus (FK506) blocks both cellular processes. These findings support the idea that drug-induced structural and functional plasticity of dendritic spines is mediated by divergent, but interactive, signaling pathways.

Ischemic strokes in children and young adults are fortunately rare. Contrasted with adult ischemic strokes, pediatric stroke etiologies vary greatly and are often unknown. Childhood lacunar strokes and trauma-induced strokes represent particularly uncommon subsets and have been reported infrequently in the literature. It is unique to find a combination of the 2-a lacunar stroke induced by trauma. Underreporting of these trauma-induced ischemic strokes could be responsible for perpetuating the lack of recognition. Here we present a lacunar stroke in a young woman associated with a water sport accident and explore relevant literature encircling deep brain ischemia coinciding with trauma.