Dramatic increases in hippocampal spine synapse density are known to occur within minutes of estrogen exposure. Until now, it has been assumed that enhanced spinogenesis increased excitatory input received by the CA1 pyramidal neurons, but how this facilitated learning and memory was unclear. Delivery of 17β-estradiol or an estrogen receptor (ER)-α (but not ER-β) agonist into the dorsal hippocampus rapidly improved general discrimination learning in female mice. The same treatments increased CA1 dendritic spines in hippocampal sections over a time course consistent with the learning acquisition phase. Surprisingly, estrogen-activated spinogenesis was associated with a decrease in CA1 hippocampal excitatory input, rapidly and transiently reducing CA1 AMPA activity via a mechanism likely reflecting AMPA receptor internalization and creation of silent or immature synapses. We propose that estrogens promote hippocampally mediated learning via a mechanism resembling some of the broad features of normal development, an initial overproduction of functionally immature connections being subsequently "pruned" by experience.immature synapse | short-term memory | structural plasticity | synaptic plasticity | signal-to-noise ratio E stradiol rapidly and dramatically increases hippocampal dendritic spine and synapse density within minutes of application (1-4). There is a strong correlative association between estrogeninduced spinogenesis and improvements in cognition (5); however, the relationship of these structural changes to estrogen-induced alterations in hippocampal function is unclear. Our laboratory recently reported that the density of hippocampal CA1 pyramidal dendritic spines increases very rapidly after systemic treatment with 17β-estradiol or estrogen receptor (ER) -selective agonists in ovariectomized female mice, changes that are paralleled by learning enhancements (2, 3). Estrogen-induced rapid structural changes are substantial, increasing spine density by 30-50% within 15-40 min of hormone application (1-3, 6). As a result, adult rodents can experience the addition of thousands of CA1 synapses within a span of minutes after exposure to estradiol. These effects of estrogens reproduce the changes occurring during the 4-d estrous cycle of female rodents, which include the induction of CA1 spines (7).How these processes contribute to the behavioral changes observed after estradiol treatment is not understood. Estradiol enhances excitatory neurotransmission throughout the hippocampus (8-10), and activates BDNF signaling in the mossy fiber system (11). Dendritic spines turn over more rapidly in the hippocampus than in the neocortex (12), particularly in the case of estradiol-induced spines (13). Such rapid, transient, and apparently indiscriminate increases in excitatory synapse formation would seem, at first sight, to be more likely to interfere with preexisting brain circuits and impair normal information processing than to enhance cognitive function.How then, does enhancement of spine formation lead to improved ...

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Synapsin II is a member of the neuronal phosphoprotein family. These phosphoproteins are evolutionarily conserved across many organisms and are important in a variety of synaptic functions, including synaptogenesis and the regulation of neurotransmitter release. A number of genome-wide scans, meta-analyses, and genetic susceptibility studies have implicated the synapsin II gene (3p25) in the etiology of schizophrenia (SZ) and other psychiatric disorders. Further studies have found a reduction of synapsin II mRNA and protein in the prefrontal cortex in post-mortem samples from schizophrenic patients. Disruptions in the expression of this gene may cause synaptic dysfunction, which can result in neurotransmitter imbalances, likely contributing to the pathogenesis of SZ. SZ is a costly, debilitating psychiatric illness affecting approximately 1.1% of the world's population, amounting to 51 million people today. The disorder is characterized by positive (hallucinations, paranoia), negative (social withdrawal, lack of motivation), and cognitive (memory impairments, attention deficits) symptoms. This review provides a comprehensive summary of the structure, function, and involvement of the synapsin family, specifically synapsin II, in the pathophysiology of SZ and possible target for therapeutic intervention/implications.

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