Host brain environmental influences on transplanted medial ganglionic eminence progenitors.

Interneuron progenitor transplantation can ameliorate disease symptoms in a variety of neurological disorders. The strategy is based on transplantation of embryonic medial ganglionic eminence (MGE) progenitors. Elucidating how host brain environment influences the integration of interneuron progenitors is critical for optimizing this strategy across different disease states. Here, we systematically evaluated the influence of age and brain region on survival, migration, and differentiation of transplant-derived cells. We find that early postnatal MGE transplantation yields superior survival and more extensive migratory capabilities compared to transplantation during the juvenile or adult stages. MGE progenitors migrate more widely in the cortex compared to the hippocampus. Maturation to interneuron subtypes is regulated by age and brain region. MGE progenitors transplanted into the dentate gyrus sub-region of the early postnatal hippocampus can differentiate into astrocytes. Our results suggest that the host brain environment critically regulates survival, spatial distribution, and maturation of MGE-derived interneurons following transplantation. These findings inform and enable optimal conditions for interneuron transplant therapies.

Hippocampal gamma and sharp-wave ripple oscillations are altered in a Cntnap2 mouse model of autism spectrum disorder.

Impaired synaptic neurotransmission may underly circuit alterations contributing to behavioral autism spectrum disorder (ASD) phenotypes. A critical component of impairments reported in somatosensory and prefrontal cortex of ASD mouse models are parvalbumin (PV)-expressing fast-spiking interneurons. However, it remains unknown whether PV interneurons mediating hippocampal networks crucial to navigation and memory processing are similarly impaired. Using PV-labeled transgenic mice, a battery of behavioral assays, in vitro patch-clamp electrophysiology, and in vivo 32-channel silicon probe local field potential recordings, we address this question in a Cntnap2-null mutant mouse model representing a human ASD risk factor gene. Cntnap2-/- mice show a reduction in hippocampal PV interneuron density, reduced inhibitory input to CA1 pyramidal cells, deficits in spatial discrimination ability, and frequency-dependent circuit changes within the hippocampus, including alterations in gamma oscillations, sharp-wave ripples, and theta-gamma modulation. Our findings highlight hippocampal involvement in ASD and implicate interneurons as a potential therapeutical target.

Phenotypic analysis of catastrophic childhood epilepsy genes.

Genetic engineering techniques have contributed to the now widespread use of zebrafish to investigate gene function, but zebrafish-based human disease studies, and particularly for neurological disorders, are limited. Here we used CRISPR-Cas9 to generate 40 single-gene mutant zebrafish lines representing catastrophic childhood epilepsies. We evaluated larval phenotypes using electrophysiological, behavioral, neuro-anatomical, survival and pharmacological assays. Local field potential recordings (LFP) were used to screen ∼3300 larvae. Phenotypes with unprovoked electrographic seizure activity (i.e., epilepsy) were identified in zebrafish lines for 8 genes; ARX, EEF1A, GABRB3, GRIN1, PNPO, SCN1A, STRADA and STXBP1. We also created an open-source database containing sequencing information, survival curves, behavioral profiles and representative electrophysiology data. We offer all zebrafish lines as a resource to the neuroscience community and envision them as a starting point for further functional analysis and/or identification of new therapies.

Memory Deficit in an Object Location Task after Mild Traumatic Brain Injury Is Associated with Impaired Early Object Exploration and Both Are Restored by Branched Chain Amino Acid Dietary Therapy.

The relation between traumatic brain injury (TBI) and memory dysfunction is well established, yet imprecise. Here, we investigate whether mild TBI causes a specific deficit in spatial episodic memory. Fifty-eight (29 TBI, 29 sham) mice were run in a spatial recognition task. To determine which phase of memory might be affected in our task, we assessed rodent performance at three different delay times (3 min, 1 h, and 24 h). We found that sham and TBI mice performed equally well at 3 min, but TBI mice had significantly impaired spatial recognition memory after a delay time of 1 h. Neither sham nor injured mice remembered the test object locations after a 24-h delay. In addition, the TBI-specific impairment was accompanied by a decrease in exploratory behavior during the first 3 mins of the initial exposure to the test objects. These memory and exploratory behavioral deficits were linked as branched-chain amino acid (BCAA) dietary therapy restored both memory performance and normal exploratory behavior. Our findings 1) support the use of BCAA therapy as a potential treatment for mild TBI and 2) suggest that poor memory performance post-TBI is associated with a deficit in exploratory behavior that is likely to underlie the encoding needed for memory formation.

Pathophysiology and Treatment of Memory Dysfunction After Traumatic Brain Injury.

Memory is fundamental to everyday life, and cognitive impairments resulting from traumatic brain injury (TBI) have devastating effects on TBI survivors. A contributing component to memory impairments caused by TBI is alteration in the neural circuits associated with memory function. In this review, we aim to bring together experimental findings that characterize behavioral memory deficits and the underlying pathophysiology of memory-involved circuits after TBI. While there is little doubt that TBI causes memory and cognitive dysfunction, it is difficult to conclude which memory phase, i.e., encoding, maintenance, or retrieval, is specifically altered by TBI. This is most likely due to variation in behavioral protocols and experimental models. Additionally, we review a selection of experimental treatments that hold translational potential to mitigate memory dysfunction following injury.

Mild Traumatic Brain Injury Decreases Broadband Power in Area CA1.

Cognitive impairment caused by traumatic brain injury (TBI) can lead to devastating consequences for both patients and their families. The underlying neurological basis for TBI-induced cognitive dysfunction remains unknown. However, many lines of research have implicated the hippocampus in the pathophysiology of TBI. In particular, past research has found that theta oscillations, long thought to be the electrophysiological basis of learning and memory, are decreased in the hippocampus post-TBI. Here, we recorded in vivo electrophysiological activity in the hippocampi of 16 mice, 8 of which had previously undergone a TBI. Consistent with previous data, we found that theta power in the hippocampus was decreased in TBI animals compared to sham controls; however, this effect was driven by changes in broadband power and not theta oscillations. This result suggests that broadband fluctuations in the hippocampal local field potential can be used as an electrophysiological surrogate of abnormal neurological activity post-TBI.

Traumatic brain injury in an aging population.

The epidemiology of traumatic brain injury (TBI) is changing in several Western countries, with an increasing proportion of elderly TBI patients admitted to the intensive care unit (ICU). We describe a series of 1366 adult patients admitted to three neuro-ICUs in which 44% of cases were 50 years of age or older. The health status before trauma (rated using the APACHE score) was worse in older patients. In all 604 patients had emergency removal of intracranial masses, with extradural hematomas more frequent in young cases and subdural hematomas more frequent in older patients. Outcomes were classified according to the Glasgow Outcome Scale (GOS) 6 months post-trauma, as favorable (GOS score 4-5), or unfavorable (GOS score 1-3). Favorable outcomes were achieved by 50% of patients, but the proportions of unfavorable outcomes rose with age. Mortality was the main cause of unfavorable outcomes 6 months after injury in older patients. Logistic regression analysis indicates that several parameters independently contributed to outcome, including the motor component of the Glasgow Coma Scale (GCS), pupils, CT findings, and early hypotension. Additionally, the odds ratios were very high for age and health status before TBI. Patients admitted to the ICU are increasingly older, have co-morbidities, and have specific types of intracranial lesions. Early rescue, surgical treatment, and intensive care of these patients may produce excellent results up to the age of 59 years, with favorable outcomes still possible for 39% of cases aged 60-69 years, without an excessive burden of severely disabled patients.