Genetic targeting of NRXN2 in mice unveils role in excitatory cortical synapse function and social behaviors.

Human genetics has identified rare copy number variations and deleterious mutations for all neurexin genes (NRXN1-3) in patients with neurodevelopmental diseases, and electrophysiological recordings in animal brains have shown that Nrxns are important for synaptic transmission. While several mouse models for Nrxn1α inactivation have previously been studied for behavioral changes, very little information is available for other variants. Here, we validate that mice lacking Nrxn2α exhibit behavioral abnormalities, characterized by social interaction deficits and increased anxiety-like behavior, which partially overlap, partially differ from Nrxn1α mutant behaviors. Using patch-clamp recordings in Nrxn2α knockout brains, we observe reduced spontaneous transmitter release at excitatory synapses in the neocortex. We also analyse at this cellular level a novel NRXN2 mouse model that carries a combined deletion of Nrxn2α and Nrxn2ß. Electrophysiological analysis of this Nrxn2-mutant mouse shows surprisingly similar defects of excitatory release to Nrxn2α, indicating that the ß-variant of Nrxn2 has no strong function in basic transmission at these synapses. Inhibitory transmission as well as synapse densities and ultrastructure remain unchanged in the neocortex of both models. Furthermore, at Nrxn2α and Nrxn2-mutant excitatory synapses we find an altered facilitation and N-methyl-D-aspartate receptor (NMDAR) function because NMDAR-dependent decay time and NMDAR-mediated responses are reduced. As Nrxn can indirectly be linked to NMDAR via neuroligin and PSD-95, the trans-synaptic nature of this complex may help to explain occurrence of presynaptic and postsynaptic effects. Since excitatory/inhibitory imbalances and impairment of NMDAR function are alledged to have a role in autism and schizophrenia, our results support the idea of a related pathomechanism in these disorders.

Intracellular and extracellular roles for tau in neurodegenerative disease.

Tau has a well-established role as a microtubule-associated protein, in which it stabilizes the neuronal cytoskeleton. This function of tau is influenced by tau phosphorylation state, which is significantly increased in Alzheimer's disease and related tauopathies. Disruptions to the cytoskeleton in disease-affected neurons include reduced length and numbers of stable microtubules, and their diminished stability is associated with increased tau phosphorylation in disease. Tau is also localized in the nucleus and plasma membrane of neurons, where it could have roles in DNA repair and cell signaling. Most recently, potential roles for extracellular tau have been highlighted. The release of tau from neurons is a physiological process that can be regulated by neuronal activity and extracellular tau may play a role in inter-neuronal signaling. In addition, recent studies have suggested that the misfolding of tau in diseased brain leads to abnormal conformations of tau that can be taken up by neighboring neurons. Such a mechanism may be responsible for the apparent prion-like spreading of tau pathology through the brain, which occurs in parallel with clinical progression in the tauopathies. The relationship between tau localization in neurons, tau release, and tau uptake remains to be established, as does the function of extracellular tau. More research is needed to identify disease mechanisms that drive the release and propagation of pathogenic tau and to determine the impact of extracellular tau on cognitive decline in neurodegenerative disease.

Twelve-month safety and visual acuity results from a feasibility study of intraocular, epiretinal radiation therapy for the treatment of subfoveal CNV secondary to AMD.

PURPOSE: The purpose of this study was to evaluate the short-term safety and feasibility of intraocular, epiretinal delivery of beta radiation for the treatment of subfoveal choroidal neovascularization secondary to age-related macular degeneration for 12 months. A 3-year follow-up period is planned to assess the long-term safety of the procedure. METHODS: In this nonrandomized, multicenter feasibility study, 34 treatment-naïve patients with predominantly classic, minimally classic, or occult lesions due to subfoveal choroidal neovascularization secondary to age-related macular degeneration received a single treatment with either 15 Gray (Gy) (8 patients) or 24 Gy (26 patients) beta radiation (strontium-90) using a novel intraocular delivery device. Adverse events and safety endpoints were observed and recorded. Visual acuity was measured preoperatively and postoperatively using standard Early Treatment Diabetic Retinopathy Study vision charts. RESULTS: Twelve months after treatment, no adverse events associated with exposure to radiation were observed. All patients in both 15 Gy (n = 4) and 24 Gy cohorts (n = 17) who met inclusion criteria and were treated according to protocol lost fewer than three lines of vision. Fifty percent (2/4) of the 15 Gy-treated patients and 76% (13/17) of the 24 Gy-treated patients improved or maintained their visual acuity at 12 months. In the 24 Gy group, 29% (5/17) gained three lines or more in visual acuity. The mean change in visual acuity observed at month 12 was +10.3 letters in the 24 Gy study cohort and -1.0 letters in the 15 Gy cohort. CONCLUSION: The short-term safety and efficacy of intraocular, epiretinal delivery of beta radiation for the treatment of subfoveal choroidal neovascularization was promising in this small study group and should be studied in a larger cohort of patients.