Mental health and service use of parents with and without borderline intellectual functioning.

BACKGROUND: People with borderline intellectual functioning (BIF) encounter greater social adversities than the general population and have an increased prevalence of mental illness. However, little is known about the socio-demographic characteristics and mental health of parents with BIF. METHODS: A secondary data analysis of the Adult Psychiatric Morbidity Survey 2014 was conducted. Logistic regression models were fitted to compare differences in socio-demographic, mental health and service-use characteristics between parents and non-parents with and without BIF, and to investigate if the relationship between parent status and mental health outcomes was modified by BIF status, sex, and employment. RESULTS: Data from 6872 participants was analyzed; 69.1% were parents. BIF parents had higher odds of common mental disorder, severe mental illness, post-traumatic stress disorder, self-harm/suicide and were more likely to see their General Practitioner (GP) and to receive mental health treatment than non-BIF parents. BIF parents did not have a higher prevalence of mental health problems than BIF non-parents. Being a parent, after adjusting for BIF status and other confounders, was associated with increased odds of having a common mental disorder, visits to see a GP and treatment for mental health. Female parents had higher odds of treatment for mental health problems. CONCLUSIONS: Being a parent is associated with elevated rates of common mental disorders. There is a higher burden of mental health problems and service use in people with BIF. A greater provision of specialist support services including ascertainment is indicated for this group.

Adapting the EQ-5D-3L for adults with mild to moderate learning disabilities.

BACKGROUND: Approximately 1.5 million adults in the UK have a learning disability. The difference between age at death for this group and the general population is 26 years for females and 22 years for males. The NHS Long Term Plan (January 2019) recognises learning disabilities as a clinical priority area. People with a learning disability are often excluded from research by design or lack of reasonable adjustments, and self-reported health status/health-related quality of life questionnaires such as the EQ-5D are often not appropriate for this population. Here, we systematically examine the EQ-5D-3L (its wording, content, and format) using qualitative methods to inform the adaption of the measure for use with adults with mild to moderate learning disabilities. METHODS: Think-aloud interviews with carers/advocates of learning-disabled adults were undertaken to explore the difficulties with completing the EQ-5D-3L. Alternative wording, language, structure, and images were developed using focus groups, stakeholder reference groups, and an expert panel. Data analysis followed a framework method. RESULTS: The dimensions and levels within the EQ-5D-3L were deemed appropriate for adults with mild to moderate learning disabilities. Consensus on wording, structure, and images was reached through an iterative process, and an adapted version of the EQ-5D-3L was finalised. CONCLUSION: The EQ-5D-3L adapted for adults with mild to moderate intellectual/learning disabilities can facilitate measurement of self-reported health status. Research is underway to assess the potential use of the adaptation for economic evaluation.

The development of number line estimation in children at risk of mathematics learning difficulties: A longitudinal study.

Children with mathematics learning difficulties (MLD) show poorer performance on the number line task, but how performance on this task relates to other mathematical skills is unclear. This study examined the association between performance on the number line task and mathematical skills during the first 2 years of school for children at risk of MLD. Children (N = 100; Mage = 83.63 months) were assessed on four occasions on the number line task and other mathematical skills (math fluency, numerical operations, and mathematical reasoning). Estimation patterns were analyzed based on the representational shift and proportional judgment accounts separately. More consistent longitudinal trends and stronger evidence for differences in mathematical skills based on estimation patterns were found within the representational shift account. Latent growth curve models showed accuracy on the number line task as a predictor of growth in some mathematical skills assessed. We discuss impacts of methodological limitations on the study of estimation patterns.

'Moving on' for Adults With a Learning Disability and Their Families: A Constructivist Grounded Theory Study.

Ending familial co-residence, termed 'moving on' by participants, is an increasingly relevant life transition for people with a learning disability due to increasing life expectancy and policy developments. Nevertheless, there is an absence of research exploring this transition experience in a United Kingdom (UK) context. This constructivist grounded theory study therefore aimed to explore, conceptualise, and theorise the 'moving on' experiences of adults with a learning disability and their families. This article reports the experiences of five adults with a learning disability and nine family members in England, UK. Narrative interviews and creative storybook methods were used to collect data between April 2015 and May 2016. Constant comparative methods, theoretical sampling, and memo writing were used throughout data collection and analysis. Participants with a learning disability presented personal growth and greater life fulfilment over the course of the transition; they flourished. In parallel, family members relinquished their care responsibilities. Importantly, the iterative and reciprocal relationship between flourishing and relinquishing shows that ongoing family member involvement is crucial during and following relocation. Family members identified factors that potentially inhibit relinquishing: pressure to 'let go', different perceptions of independence between family members and service providers, inadequate future investment, and rapport with professional carers. These novel insights led to the generation of the first known mid-range theory concerning this transition, entitled 'Moving on: flourishing and relinquishing'. Findings will guide future research in this field and facilitate the design of appropriate support for people with a learning disability and their families.

Subtypes of mathematical learning disability and their antecedents: A cognitive diagnostic approach.

Using cognitive diagnostic modeling (CDM), this study identified subtypes of mathematics learning disability (MLD) based on children's numerical skills and examined the language and spatial precursors of these subtypes. Participants were 99 MLD children and 420 low achievers identified from 1839 Finnish children (966 boys) who were followed from preschool (age 6) to fourth grade (2007-2011). Five subtypes were identified: the arithmetic fluency deficit only subtype, the counting deficit subtype, the pervasive deficit subtype, the symbolic deficit subtype, and the counting and concept deficit subtype. Different subtypes depended on different constellations of language and spatial deficits. Findings highlight the effectiveness of CDM in identifying MLD subtypes and underscore the importance of understanding the specific deficits and antecedents of the subtypes.

How can we make self-sampling packs for sexually transmitted infections and bloodborne viruses more inclusive? A qualitative study with people with mild learning disabilities and low health literacy.

OBJECTIVES: 1.5 million people in the UK have mild to moderate learning disabilities. STIs and bloodborne viruses (BBVs) are over-represented in people experiencing broader health inequalities, which include those with mild learning disabilities. Self-managed care, including self-sampling for STIs/BBVs, is increasingly commonplace, requiring agency and health literacy. To inform the development of a partner notification trial, we explored barriers and facilitators to correct use of an STI/BBV self-sampling pack among people with mild learning disabilities. METHODS: Using purposive and convenience sampling we conducted four interviews and five gender-specific focus groups with 25 people (13 women, 12 men) with mild learning disabilities (July-August 2018) in Scotland. We balanced deductive and inductive thematic analyses of audio transcripts to explore issues associated with barriers and facilitators to correct use of the pack. RESULTS: All participants found at least one element of the pack challenging or impossible, but welcomed the opportunity to undertake sexual health screening without attending a clinic and welcomed the inclusion of condoms. Reported barriers to correct use included perceived overly complex STI/BBV information and instructions, feeling overwhelmed and the manual dexterity required for blood sampling. Many women struggled interpreting anatomical diagrams depicting vulvovaginal self-swabbing. Facilitators included pre-existing STI/BBV knowledge, familiarity with self-management, good social support and knowing that the service afforded privacy. CONCLUSION: In the first study to explore the usability of self-sampling packs for STI/BBV in people with learning disabilities, participants found it challenging to use the pack. Limiting information to the minimum required to inform decision-making, 'easy read' formats, simple language, large font sizes and simpler diagrams could improve acceptability. However, some people will remain unable to engage with self-sampling at all. To avoid widening health inequalities, face-to-face options should continue to be provided for those unable or unwilling to engage with self-managed care.

Variants in the SK2 channel gene (KCNN2) lead to dominant neurodevelopmental movement disorders.

KCNN2 encodes the small conductance calcium-activated potassium channel 2 (SK2). Rodent models with spontaneous Kcnn2 mutations show abnormal gait and locomotor activity, tremor and memory deficits, but human disorders related to KCNN2 variants are largely unknown. Using exome sequencing, we identified a de novo KCNN2 frameshift deletion in a patient with learning disabilities, cerebellar ataxia and white matter abnormalities on brain MRI. This discovery prompted us to collect data from nine additional patients with de novo KCNN2 variants (one nonsense, one splice site, six missense variants and one in-frame deletion) and one family with a missense variant inherited from the affected mother. We investigated the functional impact of six selected variants on SK2 channel function using the patch-clamp technique. All variants tested but one, which was reclassified to uncertain significance, led to a loss-of-function of SK2 channels. Patients with KCNN2 variants had motor and language developmental delay, intellectual disability often associated with early-onset movement disorders comprising cerebellar ataxia and/or extrapyramidal symptoms. Altogether, our findings provide evidence that heterozygous variants, likely causing a haploinsufficiency of the KCNN2 gene, lead to novel autosomal dominant neurodevelopmental movement disorders mirroring phenotypes previously described in rodents.

Administration of Selenium Nanoparticles Reverses Streptozotocin-Induced Neurotoxicity in the male rats.

Alzheimer's disease is the most common neurodegenerative disease associated with deposition of amyloid-beta and the increased oxidative stress. High free radical scavenging ability of selenium nanoparticles (SeNPs) has been acknowledged, so in the present study, the effects of treatment with SeNPs on Streptozotocin (STZ)-induced neurotoxicity were evaluated in the male rats. Learning and memory impairment was induced by intraventricular injection of STZ. Following induction of memory impairment, the rats received 0.4 mg/kg of SeNPs daily for one month. Memory function, antioxidant capacity, and deposition of Amyloid ß (Aß) were assessed using the shuttle box task, biochemical methods, and Congo red staining. Injection of STZ caused memory impairment, a decrease in the level of total thiol group (TTG), and an increase in the malondialdehyde (MDA) content and deposition of Aß. Administration of SeNPs reversed the neurotoxicity induced by STZ. It seems that SeNPs likely had neuroprotective effects on the animal model of Alzheimer's disease through increasing antioxidants҆ capacity.

Cognitive and non-cognitive factors in educational and occupational outcomes-Specific to reading disability?

Low education and unemployment are common adult-age outcomes associated with childhood RD (c-RD). However, adult-age cognitive and non-cognitive factors associated with different outcomes remain unknown. We studied whether these outcomes are equally common among individuals with c-RD and controls and whether these outcomes are related to adult-age literacy skills or cognitive and non-cognitive factors or their interaction with c-RD. We examined adult participants with c-RD (n = 48) and their matched controls (n = 37). Low education was more common among c-RD than the controls, whereas long-term unemployment was equally common in both groups. Moreover, adult-age literacy skills, cognitive skills and non-cognitive factors were related to both low education and long-term unemployment. Only a few c-RD-specific associations emerged: c-RD, especially in interaction with low verbal or reading comprehension, was associated with low education, and c-RD in interaction with slow adult-age reading was associated with long-term unemployment. Avoidant coping style, emotional wellbeing and social functioning were related to education, and life-satisfaction to unemployment irrespective of c-RD. Thus, the non-cognitive factors associated with education and employment are similar in individuals with and without c-RD. Special attention should be paid to training c-RD individuals in basic academic, social and emotional skills.

Improving cognitive functions in adolescents with learning difficulties: A feasibility study on the potential use of telerehabilitation during Covid-19 pandemic in Italy.

INTRODUCTION: Learning disabilities are due to genetic and/or neurobiological factors that alter brain functioning by affecting one or more cognitive processes related to learning. This study aimed to assess the efficacy of cognitive telerehabilitation in adolescents with learning disabilities to overcome the treatment problems related to the COVID-19 pandemic lockdown. METHODS: Twenty-four patients diagnosed with Unspecified Learning Disability (mean ± SD age: 18.2 ± 2.9 years; 50% male) were enrolled in this study. The patients were assessed by a neuropsychological evaluation at the beginning and at the end of the program. All patients received cognitive treatment via a specific telehealth app to stimulate the cognitive skills related to learning. The treatment lasted four weeks, with a daily training (lasting up to 60 min), for five days a week. RESULTS: Our young patients reported a statistically significant improvement in the main cognitive domains that are usually compromised in learning disabilities, including sustained and selective attention, shifting of attention, control of interference, memory and speed of information processing. Moreover, the patients showed a good usability and motivation during the training. CONCLUSIONS: Our study has shown that telerehabilitation could be a valid tool for the rehabilitation of specific cognitive skills in adolescents with learning difficulties.

The mechanism of enriched environment repairing the learning and memory impairment in offspring of prenatal stress by regulating the expression of activity-regulated cytoskeletal-associated and insulin-like growth factor-2 in hippocampus.

BACKGROUND: Prenatal stress can cause neurobiological and behavioral defects in offspring; environmental factors play a crucial role in regulating the development of brain and behavioral; this study was designed to test and verify whether an enriched environment can repair learning and memory impairment in offspring rats induced by prenatal stress and to explore its mechanism involving the expression of insulin-like growth factor-2 (IGF-2) and activity-regulated cytoskeletal-associated protein (Arc) in the hippocampus of the offspring. METHODS: Rats were selected to establish a chronic unpredictable mild stress (CUMS) model during pregnancy. Offspring were weaned on 21st day and housed under either standard or an enriched environment. The learning and memory ability were tested using Morris water maze and Y-maze. The expression of IGF-2 and Arc mRNA and protein were respectively measured by using RT-PCR and Western blotting. RESULTS: There was an elevation in the plasma corticosterone level of rat model of maternal chronic stress during pregnancy. Maternal stress's offspring exposed to an enriched environment could decrease their plasma corticosterone level and improve their weight. The offspring of maternal stress during pregnancy exhibited abnormalities in Morris water maze and Y-maze, which were improved in an enriched environment. The expression of IGF-2, Arc mRNA, and protein in offspring of maternal stress during pregnancy was boosted and some relationships existed between these parameters after being exposed enriched environment. CONCLUSIONS: The learning and memory impairment in offspring of prenatal stress can be rectified by the enriched environment, the mechanism of which is related to the decreasing plasma corticosterone and increasing hippocampal IGF-2 and Arc of offspring rats following maternal chronic stress during pregnancy.

AMPA Receptor Dysregulation and Therapeutic Interventions in a Mouse Model of CDKL5 Deficiency Disorder.

Pathogenic mutations in cyclin-dependent kinase-like 5 (CDKL5) result in CDKL5 deficiency disorder (CDD), a rare disease marked by early-life seizures, autistic behaviors, and intellectual disability. Although mouse models of CDD exhibit dendritic instability and alterations in synaptic scaffolding proteins, studies of glutamate receptor levels and function are limited. Here we used a novel mouse model of CDD, the Cdkl5R59X knock-in mouse (R59X), to investigate changes in synaptic glutamate receptor subunits and functional consequences. Male mice were used for all experiments to avoid the confounding effects of X-inactivation that would be present in female heterozygous mice. We showed that adult male R59X mice recapitulated the behavioral outcomes observed in other mouse models of CDD, including social deficits and memory and learning impairments, and exhibited decreased latency to seizure upon pentylenetetrazol administration. Furthermore, we observed a specific increase in GluA2-lacking α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid)-type glutamate receptors (AMPARs) in the adult R59X hippocampus, which is accompanied electrophysiologically by increased rectification ratio of AMPAR EPSCs and elevated early-phase long term potentiation (LTP). Finally, we showed that acute treatment with the GluA2-lacking AMPAR blocker IEM-1460 decreased AMPAR currents, and rescued social deficits, working memory impairments, and seizure behavior latency in R59X mice.SIGNIFICANCE STATEMENT CDKL5 deficiency disorder (CDD) is a rare disease marked by autistic-like behaviors, intellectual disability, and seizures. While synaptic dysfunction has been observed in mouse models of CDD, there is limited information on how synaptic alterations contribute to behavioral and functional changes in CDD. Here we reveal elevated hippocampal GluA2-lacking AMPAR expression in a novel mouse model of CDD that is accompanied by changes in synaptic AMPAR function and plasticity. We also show, for the first time, that acutely targeting GluA2-lacking AMPAR dysregulation rescues core synaptic and neurobehavioral deficits in CDD.

Lanthanum Chloride Impairs Learning and Memory and Induces Dendritic Spine Abnormality by Down-Regulating Rac1/PAK Signaling Pathway in Hippocampus of Offspring Rats.

Lanthanum (La) is a natural rare earth element. It has neurotoxic effects which can impair learning and memory in humans. However, its mechanism of neurotoxicity is unclear. Learning and memory are coordinated by dendritic spines which form tiny protruding structures on the dendritic branches of neurons. This study investigated the effect of LaCl3 exposure to pregnant and lactating rats on the offspring rats' learning and memory ability. In this study, rats were divided into 4 groups and given distilled water solution containing 0%, 0.125%, 0.25%, 0.5% LaCl3, respectively, and this was done from conception to the end of the location. The effects of LaCl3 on spatial learning and memory ability in offspring rats and in the development of dendritic spines in CA1 pyramidal cells were investigated. The results showed that LaCl3 impaired spatial learning and memory ability in offspring rats, and decreased dendritic spine density during development. In addition, LaCl3 can affect the expression of CaMKII, miRNA132, p250GAP, Tiam1, PARD3, and down-regulated the activation of Rac1 which led to a decrease in the expression of Rac1/PAK signaling pathway and downstream regulatory proteins Cortactin and actin-related protein 2/3 complex (Arp2/3 complex). This study indicated that the learning and memory impairment and the decrease of dendritic spine density in the offspring of LaCl3 exposure may be related to the down-regulation of the Rac1/PAK signaling pathway regulated by Tiam1 and p250GAP.

Neurodevelopmental, behavioral, and emotional symptoms in Becker muscular dystrophy.

INTRODUCTION: Becker muscular dystrophy (BMD) results in decreased dystrophin with implications for mental health. METHODS: This is a retrospective case series of neurodevelopmental, behavioral, and emotional symptoms and respective pharmacotherapies of 70 patients with BMD. RESULTS: Fifty-four (77.1%) patients exhibited at least one symptom, and 19 (27.1%) patients exhibited four or more symptoms. The most prevalent symptoms were specific learning disabilities or special education needs (31.4%), inattention/hyperactivity (35.7%), language/speech delays (35.7%), and emotional or behavioral dysregulation (38.6%). Fisher's exact tests indicated that anxiety was more prevalent with mutations upstream of exon 30 (P = .049), but the prevalence of other symptoms did not differ with respect to mutation sites. Similarly, the number of symptoms individual patients with BMD exhibited did not differ with respect to mutation sites. Seventeen (24.3%) patients required pharmacotherapy to manage symptoms. DISCUSSION: Neurodevelopmental, behavioral, and emotional symptoms are prevalent in patients with BMD regardless of dystrophin gene mutation site.

Effect of Curcuma zedoaria hydro-alcoholic extract on learning, memory deficits and oxidative damage of brain tissue following seizures induced by pentylenetetrazole in rat.

BACKGROUND: Previous studies have shown that seizures can cause cognitive disorders. On the other hand, the Curcuma zedoaria (CZ) has beneficial effects on the nervous system. However, there is little information on the possible effects of the CZ extract on seizures. The aim of this study was to investigate the possible effects of CZ extract on cognitive impairment and oxidative stress induced by epilepsy in rats. METHODS: Rats were randomly divided into different groups. In all rats (except the sham group), kindling was performed by intraperitoneal injection of pentylenetetrazol (PTZ) at a dose of 35 mg/kg every 48 h for 14 days. Positive group received 2 mg/kg diazepam + PTZ; treatment groups received 100, 200 or 400 mg/kg CZ extract + PTZ; and one group received 0.5 mg/kg flumazenil and CZ extract + PTZ. Shuttle box and Morris Water Maze tests were used to measure memory and learning. On the last day of treatments PTZ injection was at dose of 60 mg/kg, tonic seizure threshold and mortality rate were recorded in each group. After deep anesthesia, blood was drawn from the rats' hearts and the hippocampus of all rats was removed. RESULTS: Statistical analysis of the data showed that the CZ extract significantly increased the tonic seizure threshold and reduced the pentylenetetrazol-induced mortality and the extract dose of 400 mg/kg was selected as the most effective dose compared to the other doses. It was also found that flumazenil (a GABAA receptor antagonist) reduced the tonic seizure threshold compared to the effective dose of the extract. The results of shuttle box and Morris water maze behavioral tests showed that memory and learning decreased in the negative control group and the CZ extract treatment improved memory and learning in rats. The CZ extract also increased antioxidant capacity, decreased MDA and NO in the brain and serum of pre-treated groups in compared to the negative control group. CONCLUSION: It is concluded that the CZ extract has beneficial effects on learning and memory impairment in PTZ-induced epilepsy model, which has been associated with antioxidant effects in the brain or possibly exerts its effects through the GABAergic system.

Reading-writing disorder in children with idiopathic epilepsy.

Several studies have documented learning disabilities (LDs) in subjects with epilepsy, who have been shown to be at greater risk of mild neuropsychological damage, with the consequent risk of academic failure. This retrospective study aimed to investigate the peculiarities of reading and writing disorders in subjects with idiopathic epilepsy. The reading and writing performance of 35 children affected by reading and writing disorders and idiopathic epilepsy (R/WD + E group) has been compared with the performance of 37 children with only reading and writing disorders (R/WD group). A comparison group of 22 typical developing healthy children (TDC group) was also included in the study. As expected, the TDC group reached better performances in the reading and writing tests administered. Between R/WD + E and R/WD groups, there was a substantial analogy in reading and writing disabilities. The differences between the two clinical groups concern writing ability in sentences dictation and verbal and visuospatial short-term memory in digit span and memory-for-location (MFL) tests.

Pediatric Migraine and Academics.

PURPOSE OF REVIEW: The purpose of this review is to examine the multitude of factors which may impact learning and academic performance in patients with pediatric migraine. RECENT FINDINGS: A range of associations of varying degree were noted between pediatric migraine and conditions such as ADHD, learning disabilities, sleep disorders, and psychiatric comorbidities with regard to headache pain and school functioning. Recent literature highlights the importance of sleep in relation to headache, mood disorders, and learning in youth and the emerging role of perfectionism. Children with migraine remain at risk for school related and learning difficulties which may be primarily due to pain, due to other medical and psychiatric comorbidities commonly found in this population, or a combination. The relationships are complex and further studies are needed to clearly elucidate the shared biological and environmental pathophysiologic mechanisms.

Are children with unrecognised psychiatric disorders being excluded from school? A secondary analysis of the British Child and Adolescent Mental Health Surveys 2004 and 2007.

BACKGROUND: There is limited research that explores the association between exclusion from school and mental health, but it seems intuitively plausible that the recognition of mental difficulties by key teachers and parents would influence the likelihood of exclusion from school. METHODS: A secondary analysis of the British Child and Adolescent Mental Health survey 2004, (n = 7997) and the 2007 follow-up (n = 5326) was conducted. Recognition of difficulty was assessed via a derived variable that combined the first item of the Impact supplement of the Strengths and Difficulties Questionnaire which asked parents and teachers if they thought that the child has difficulties with emotions, behaviour and concentration, and the presence/absence of psychiatric disorder measured by the Development and Well-being Assessment. RESULTS: Adjusted logistic regression models demonstrated that children with recognised difficulties were more likely to be excluded [adjusted odds ratio (OR) 5.78, confidence interval 3.45-9.64, p < 0.001], but children with unrecognised difficulties [adjusted OR 3.58 (1.46-8.81) p < 0.005] or recognised subclinical difficulties [adjusted OR 3.42 (2.04-5.73) p < 0.001] were also more likely to be excluded than children with no difficulties. Children with conduct disorder and attention deficit hyperactivity disorder were most likely to be excluded compared with other types of disorder. CONCLUSION: Exclusion from school may result from a failure to provide timely and effective support rather than a failure to recognise psychopathology.

Education disparities in young people with and without neurodisabilities.

AIM: To examine key outcomes in the education of young people with and without neurodisabilities, and to investigate additional disparities in educational achievement in relation to socio-economic background. METHOD: Data were collected on 2488 Canadian children (age range 10-11y) in 1994 and 1995 from the National Longitudinal Survey of Children and Youth whom were followed for 14 years. We performed separate, discrete-time survival analysis to investigate the effects of having a neurodisability on high school completion, enrolment in post-secondary education (PSE), and PSE completion. RESULTS: The baseline prevalence of neurodisabilities was 12%. Fewer children with neurodisabilities completed high school or enrolled in PSE, compared to children without neurodisabilities, irrespective of parental education. The likelihood that students with neurodisabilities completed PSE differed according to their parents' education: students with neurodisabilities living in less-educated families were about half as likely to complete PSE themselves. INTERPRETATION: Children with neurodisabilities receive less education than children without neurodisabilities. Children from families with low educational attainment appear to be particularly vulnerable. WHAT THIS PAPER ADDS: Twelve per cent of children in Canada aged 10 years to 11 years have a neurodisability. High school completion rate was 70% for children with neurodisabilities versus 94% for children without neurodisabilities. Children with neurodisabilities from less-educated families are particularly vulnerable to lower educational achievement.

Loss of TrkB Signaling in Parvalbumin-Expressing Basket Cells Results in Network Activity Disruption and Abnormal Behavior.

The GABAergic system is regulated by the brain-derived neurotrophic factor (BDNF)/Tropomyosin-related kinase B (TrkB) pathway, but the cell-intrinsic role of TrkB signaling in parvalbumin cortical interneuron development and function is unclear. We performed conditional ablation of the TrkB receptor in parvalbumin-expressing (PV) interneurons to study whether postnatal loss of TrkB in parvalbumin cells affects their survival, connectivity, spontaneous and evoked neuronal activity and behavior. Using in vivo recordings of local field potentials, we found reduced gamma oscillations in the sensory cortex of PVcre+; TrkBF/F conditional knockout mice (TrkB cKO), along with increased firing of putative excitatory neurons. There was a significant downregulation in parvalbumin neuron number in cerebral and cerebellar cortices of TrkB cKO mice. In addition, inhibitory synaptic connections between basket cells and pyramidal neurons were profoundly reduced in the neocortex of TrkB cKO mice and there was a loss of cortical volume. TrkB cKO mice also showed profound hyperactivity, stereotypies, motor deficits and learning/memory defects. Our findings demonstrate that the targeting and/or synapse formation of PV-expressing basket cells with principal excitatory neurons require TrkB signaling in parvalbumin cells. Disruption of this signaling has major consequences for parvalbumin interneuron connectivity, network dynamics, cognitive and motor behavior.