SUMMARY Spine growth and retraction with synapse formation and elimination plays an important role in shaping brain circuits during development and in the adult brain. Yet the temporal relationship between spine morphogenesis and the formation of functional synapses remains poorly defined. We imaged hippocampal pyramidal neurons to identify spines of different ages. We then used two-photon glutamate uncaging, whole-cell recording, and Ca2+ imaging to analyze the properties of nascent spines and their older neighbors. We found that new spines expressed glutamate sensitive currents that were indistinguishable from mature spines of comparable volumes. Some spines exhibited negligible AMPA receptor-mediated responses, but the occurrence of these ‘silent’ spines was uncorrelated with spine age. In contrast, NMDA receptor-mediated Ca2+ accumulations were significantly lower in new spines. New spines reconstructed using electron microscopy made synapses. Our data support a model in which outgrowth and enlargement of nascent spines is tightly coupled to formation and maturation of glutamatergic synapses.

Refinement of neural circuits in the mammalian cerebral cortex shapes brain function during development and in the adult. However, the signaling mechanisms underlying the synapse-specific shrinkage and loss of spiny synapses when neural circuits are remodeled remain poorly defined. Here, we show that low-frequency glutamatergic activity at individual dendritic spines leads to synapse-specific synaptic weakening and spine shrinkage on CA1 neurons in the hippocampus. We found that shrinkage of individual spines in response to lowfrequency glutamate uncaging is saturable, reversible, and requires NMDA receptor activation. Notably, shrinkage of large spines additionally requires signaling through metabotropic glutamate receptors (mGluRs) and inositol 1,4,5-trisphosphate receptors (IP 3 Rs), supported by higher levels of mGluR signaling activity in large spines. Our results support a model in which signaling through both NMDA receptors and mGluRs is required to drive activity-dependent synaptic weakening and spine shrinkage at large, mature dendritic spines when neural circuits undergo experience-dependent modification.two-photon microscopy | long-term depression | synaptic plasticity | spine dynamics S tructural plasticity of neurons, such as the growth and retraction of dendritic spines, is thought to contribute to the experience-dependent changes in brain circuitry that mediate learning and memory (1, 2). In particular, the destabilization and loss of spiny synapses plays a critical role in the refinement of neural circuits during development and during learning. Indeed, spine elimination occurs more frequently than does spine formation in young rodents between the first and the third month of age (3-5), a period when experience-dependent refinement of neural circuitry is in its peak. Furthermore, several in vivo studies demonstrate that manipulations leading to experience-dependent circuit plasticity also increase the rate of spine shrinkage and loss (6-9). However, it remains unclear how neural activity drives the selective shrinkage and loss of individual dendritic spines in response to sensory experience.Dendritic spines occur in a wide variety of shapes and sizes (10, 11), and their stability is strongly correlated with spine size (3, 12, 13). Small spines are in general more motile and thought to serve as substrates for plasticity, or "learning" spines; large spines are more stable and thought to serve as components of functioning neural circuits, or "memory" spines (12,14). It is the selective shrinkage and loss of individual circuit-incorporated, persistent spines that underlies experience-dependent circuit refinement (6, 9, 15). Thus, experience-dependent circuit remodeling requires an activity-dependent mechanism that selectively induces shrinkage and retraction of those specific individual dendritic spines that are no longer useful for circuit function.Previous studies have established that low-frequency glutamatergic stimulation (LFS), which causes long-term depression (LTD) of synaptic transmission in...

Clients who had completed psychotherapy were interviewed about the significant experiences and moments they recalled within their sessions. These interviews were analyzed using grounded theory, creating a hierarchy of categories that represent what clients find important in therapy. From the hermeneutic analysis of the content of these categories, a list of principles was constructed to guide the moment-to-moment process of psychotherapy practice. The authors respond to the call for qualitative outcome studies and demonstrate how qualitative psychotherapy research can lead to empirically derived principles that then can become the foundation of future research and psychotherapy integration efforts.

Learning new tasks has been associated with increased growth and stabilization of new dendritic spines. We examined whether long-term potentiation (LTP), a key cellular mechanism thought to underlie learning, plays a role in selective stabilization of individual new spines during circuit plasticity. Using two-photon glutamate uncaging, we stimulated nascent spines on dendrites of rat hippocampal CA1 neurons with patterns that induce LTP and then monitored spine survival rates using time-lapse imaging. Remarkably, we found that LTP-inducing stimuli increased the long-term survivorship (Ͼ14 h) of individual new spines. Activity-induced new spine stabilization required NMDA receptor activation and was specific for stimuli that induced LTP. Moreover, abrogating CaMKII binding to the NMDA receptor abolished activity-induced new spine stabilization. Our findings demonstrate for the first time that, in addition to enhancing the efficacy of preexisting synapses, LTP-inducing stimuli promote the transition of nascent spines from a short-lived, transient state to a longer-lived, persistent state.

OBJECTIVE A randomized trial that compares clinical outcomes following microsurgery (MS) or stereotactic radiosurgery (SRS) for patients with small- and medium-sized vestibular schwannomas (VSs) is impractical, but would have important implications for clinical decision making. A matched cohort analysis was conducted to evaluate clinical outcomes in patients treated with MS or SRS. METHODS The records of 399 VS patients who were cared for by 2 neurosurgeons and 1 neurotologist between 2001 and 2014 were evaluated. From this data set, 3 retrospective matched cohorts were created to compare hearing preservation (21 matched pairs), facial nerve preservation (83 matched pairs), intervention-free survival, and complication rates (85 matched pairs) between cases managed with SRS and patients managed with MS. Cases were matched for age at surgery (± 10 years) and lesion size (± 0.1 cm). To compare hearing outcomes, cases were additionally matched for preoperative Class A hearing according to the American Academy of Otolaryngology-Head and Neck Surgery guidelines. To compare facial nerve (i.e., cranial nerve [CN] VII) outcomes, cases were additionally matched for preoperative House-Brackmann (HB) score. Investigators who were not involved with patient care reviewed the clinical and imaging records. The reported outcomes were as assessed at the time of the last follow-up, unless otherwise stated. RESULTS The preservation of preoperative Class A hearing status was achieved in 14.3% of MS cases compared with 42.9% of SRS cases (OR 4.5; p < 0.05) after an average follow-up interval of 43.7 months and 30.3 months, respectively. Serviceable hearing was preserved in 42.8% of MS cases compared with 85.7% of SRS cases (OR 8.0; p < 0.01). The rates of postoperative CN VII dysfunction were low for both groups, although significantly higher in the MS group (HB III-IV 11% vs 0% for SRS; OR 21.3; p < 0.01) at a median follow-up interval of 35.7 and 19.0 months for MS and SRS, respectively. There was no difference in the need for subsequent intervention (2 MS patients and 2 SRS patients). CONCLUSIONS At this high-volume center, VS resection or radiosurgery for tumors ≤ 2.8 cm in diameter was associated with low overall morbidity. The need for subsequent intervention was the same in both groups. SRS was associated with improved hearing and facial preservation rates and reduced morbidity, but with a shorter average follow-up period. Facial function was excellent in both groups. Since patients were not randomly selected for surgery, different clinical outcomes may be of different value to individual patients. Both anticipated medical outcomes and patient goals remain the drivers of treatment decisions.