Frontotemporal dementia (FTD) is a neurodegenerative disease with hallmark deficits in social and emotional function. Heterozygous loss-of-function mutations in GRN, the progranulin gene, are a common genetic cause of the disorder, but the mechanisms by which progranulin haploinsufficiency causes neuronal dysfunction in FTD are unclear. Homozygous progranulin knockout (Grn−/−) mice have been studied as a model of this disorder and show behavioral deficits and a neuroinflammatory phenotype with robust microglial activation. However, homozygous GRN mutations causing complete progranulin deficiency were recently shown to cause a different neurological disorder, neuronal ceroid lipofuscinosis, suggesting that the total absence of progranulin may have effects distinct from those of haploinsufficiency. Here, we studied progranulin heterozygous (Grn+/−) mice, which model progranulin haploinsufficiency. We found that Grn+/− mice developed age-dependent social and emotional deficits potentially relevant to FTD. However, unlike Grn−/− mice, behavioral deficits in Grn+/− mice occurred in the absence of gliosis or increased expression of tumor necrosis factor–α. Instead, we found neuronal abnormalities in the amygdala, an area of selective vulnerability in FTD, in Grn+/− mice. Our findings indicate that FTD-related deficits due to progranulin haploinsufficiency can develop in the absence of detectable gliosis and neuroinflammation, thereby dissociating microglial activation from functional deficits and suggesting an important effect of progranulin deficiency on neurons.

Loss-of-function mutations in progranulin (GRN) are a major autosomal dominant cause of frontotemporal dementia (FTD), a neurodegenerative disorder in which social behavior is disrupted. Progranulin-insufficient mice, both Grn+/− and Grn−/−, are used as models of FTD due to GRN mutations, with Grn+/− mice mimicking the progranulin haploinsufficiency of FTD patients with GRN mutations. Grn+/− mice have increased social dominance in the tube test at 6 months of age, though this phenotype has not been reported in Grn−/− mice. In this study, we investigated how the tube test phenotype of progranulin-insufficient mice changes with age, determined its robustness under several testing conditions, and explored associated cellular mechanisms. We observed biphasic social dominance abnormalities in Grn+/− mice: at 6–8 months, Grn+/− mice were more dominant than wild-type littermates, while after 9 months of age, Grn+/− mice were less dominant. In contrast, Grn−/− mice did not exhibit abnormal social dominance, suggesting that progranulin haploinsufficiency has distinct effects from complete progranulin deficiency. The biphasic tube test phenotype of Grn+/− mice was associated with abnormal cellular signaling and neuronal morphology in the amygdala and prefrontal cortex. At 6–9 months, Grn+/− mice exhibited increased mTORC2/Akt signaling in the amygdala and enhanced dendritic arbors in the basomedial amygdala, and at 9–16 months Grn+/− mice exhibited diminished basal dendritic arbors in the prelimbic cortex. These data demonstrate a progressive change in tube test dominance in Grn+/− mice and show that partial, but not complete progranulin deficiency disrupts this behavior in mice.

Frontotemporal dementia (FTD) is a neurodegenerative behavioral disorder that selectively affects the salience network, including the ventral striatum and insula. Tau mutations cause FTD, but how mutant tau impairs the salience network is unknown. Here, we address this question using a mouse model expressing the entire human tau gene with an FTD-associated mutation (V337M). Mutant, but not wild-type, human tau transgenic mice had aging-dependent repetitive and disinhibited behaviors, with synaptic deficits selectively in the ventral striatum and insula. There, mutant tau depleted PSD-95, resulting in smaller postsynaptic densities and impaired synaptic localization of NMDA receptors (NMDARs). In the ventral striatum, decreased NMDAR-mediated transmission reduced striatal neuron firing. Pharmacologically enhancing NMDAR function with the NMDAR co-agonist cycloserine reversed electrophysiological and behavioral deficits. These results indicate that NMDAR hypofunction critically contributes to FTD-associated behavioral and electrophysiological alterations and that this process can be therapeutically targeted by a Food and Drug Administration-approved drug.

Background Thousands of neurosurgical emergencies are transferred yearly to tertiary care facilities to assume a higher level of care. Several studies have examined how neurosurgical transfers influence patient outcomes, but characteristics of potentially avoidable transfers have yet to be investigated. Objective To identify whether potentially avoidable transfers represent a significant portion of transfers to a tertiary neurosurgical facility. Methods In this cohort study, we evaluated 916 neurosurgical patients transferred to a tertiary care facility over a 2-year period. Transfers were classified as potentially avoidable when no neurosurgical diagnostic test, intervention, or intensive monitoring was deemed necessary (n=180). The remaining transfers were classified as justifiable (n=736). The main outcomes and measures were age, sex, diagnosis, insurance status, intervention, distance of transfer, length of hospital and intensive care unit (ICU) stay, mortality, discharge disposition, and cost. Results Nearly 20% of transfers were identified as being potentially avoidable. While some of these patients had suffered devastating, irrecoverable neurologic insults, many had innocuous conditions that did not require transfer to a higher level of care. Justifiable transfers tend to involve patients with non-traumatic intracranial hemorrhage and cranial neoplasm. Both groups were admitted to the intensive care unit at the same rate (approximately 70% of patients). Finally, the direct transportation cost of potentially avoidable transfers was $1.46 million over 2 years. Conclusion This study identified frequency and expense of potentially avoidable transfers. There is a need for closer examination of the clinical and financial implications of potentially avoidable transfers.