Biology subjects

Al Abed, A. S.

Publications and source records attributed to Al Abed, A. S..

6 recordsLinked to original sources

bioRxiv2024

Maladaptation of Memory Systems Impairs Dorsal CA1-Dependent Temporal Binding and Declarative Memory in The Cntnap2 Knockout Mouse Model of Autism

Growing evidence implicates the hippocampus in the pathophysiology of autism spectrum disorder, particularly in the domains of social interactions and cognition. Yet, the mechanisms driving hippocampal-dependent cognitive atypicalities in autism remain poorly defined. Here, we characterized how dysfunction of the CA1 subfield of the dorsal hippocampus drives critical components of declarative memory. Using trace fear conditioning in the Cntnap2 knockout mouse model of autism, we found that capabilities to retain the association of temporally distant stimuli (i.e. temporal binding) were reduced relative to wildtype mice. Fiber photometry and optogenetic experiments demonstrated that reduced CA1 activity during temporal gaps underlies this impairment, linking CA1 dysfunction to a deficit of long-term memory retention in autism. Using a relational/declarative memory task, we also revealed a deficit in flexible spatial memory, and a preferential use of egocentric learning strategy. This unflexible learning strategy resulted from the imbalance between memory system activity, promoting frontostriatal-dependent procedural learning instead of dorsal CA1/hippocampus-dependent relational/declarative memory. Overall, this study establishes dorsal CA1 dysfunction as a circuit-level mechanism underlying cognitive inflexibility in autism, providing a neurobiological framework for hippocampal-dependent memory deficits in the condition.

neuroscience↗

bioRxiv2024

Glutamine Transport via Neurotransmitter Transporter 4 (NTT4, SLC6A17) Maintains Presynaptic Glutamate Supply at Excitatory Synapses in the Central Nervous System

The glutamate-glutamine cycle is thought to be the principle metabolic pathway that recycles glutamate at excitatory synapses. In this cycle, synaptically released glutamate is sequestered by astrocytes and converted to glutamine before being returned to the presynaptic terminal for conversion back into glutamate to replenish the neurotransmitter pool. While many aspects of this cycle have been extensively studied, a key component remains unknown: the nature of the transporter responsible for the presynaptic uptake of glutamine. We hypothesise that neurotransmitter transporter 4 (NTT4/SLC6A17) plays this role. Accordingly, we generated NTT4 knockout mice to assess its contribution to presynaptic glutamine transport and synaptic glutamate supply. Using biochemical tracing of [1-13C] glucose and [1,2-13C] acetate in awake mice, we observe a reduction of neuronal glutamate supply when NTT4 is absent. In addition, direct electrical recording of hippocampal mossy fibre boutons reveals a presynaptic glutamine transport current that is entirely inhibited by genetic or pharmacological elimination of NTT4. The role of NTT4 in neurotransmission was demonstrated by electrophysiological recordings in acute hippocampal slices, which reveal that NTT4 is required to maintain vesicular glutamate content and to sustain adequate levels of glutamate supply during periods of high-frequency neuronal activity. Finally, behavioural studies in mice demonstrate a deficit in trace fear conditioning; a hippocampus-dependent memory paradigm, and abnormalities in nest building, anxiety behaviour, and social preference. These results demonstrate that NTT4 is a presynaptic glutamine transporter which is a central component of the glutamate-glutamine cycle. NTT4 and hence the glutamate-glutamine cycle maintain neuronal glutamate supply for excitatory neurotransmission during high-frequency synaptic activity, and are key regulators of memory retention and normal behaviour.

neuroscience↗

bioRxiv2024

The correct temporal connectivity of the DG CA3 circuits involved in declarative memory processes depends on Vangl2-dependent planar cell polarity signaling

In the hippocampus, dentate gyrus granule cells connect to CA3 pyramidal cells via their axons, the mossy fibers (Mf). The synaptic terminals of Mfs (Mf boutons, MfBs) form large and complex synapses with thorny excrescences (TE) on the proximal dendrites CA3 pyramidal cells (PCs). MfB/TE synapses have distinctive "detonator" properties due to low intitial release probability and large presynaptic facilitation. The molecular mechanisms shaping the morpho-functional properties of MfB/TE synapses are still poorly understood, though alterations in their morphology are associated with Down syndrome, intellectual disabilities, and Alzheimers disease. Here, we identify the core PCP gene Vangl2 as essential to the morphogenesis and function of MfB/TE synapses. Vangl2 colocalises with the presynaptic heparan sulfate proteoglycan glypican 4 (GPC4) to stabilise the postsynaptic orphan receptor GPR158. Embryonic loss of Vangl2 disrupts the morphology of MfBs and TEs, impairs ultrastructural and molecular organisation, resulting in defective synaptic transmission and plasticity. In adult, the early loss of Vangl2 results in a number of hippocampus-dependent memory deficits including characteristic flexibility of declarative memory, organisation and retention of working/ everyday-like memory. These deficits also lead to abnormal generalisation of memories to salient cues and diminished ability to form detailed contextual memories. Together, these results establish Vangl2 as a key regulator of DG-CA3 connectivity and functions. HighlightsO_LIVangl2 is a key regulator of MfB/TE synapses morphogenesis and plasticity in CA3 C_LIO_LIVangl2-mediated GPC4-GPR158 interaction maintains MfB-TE pre-synaptic morphology and function C_LIO_LIVangl2 deletion affects declarative memory in adult mice C_LIO_LIVangl2 function is necessary for contextual learning and its loss leads toa maladaptive fear memory for salient cues C_LI

neuroscience↗

bioRxiv2023

To deliberate, remember; to anticipate, forget: Cognitive deliberation profiles underpinning active forgetting-dependent everyday-like memory performance in young and aged mice.

Recalling a specific past episode that will enable us to decide which action is suited to a given present situation is a core element of everyday life. A wealth of research has demonstrated that such selective remembering is dependent upon a capacity to inhibit or provisionally forget related yet inappropriate memory episodes which could orient behavior in unwilled directions. Everyday-like memory (EdM) refers to this type of common organizational mnemonic capacity, known to deteriorate significantly with age, putatively as a result of decline in the cognitive capacity for selective inhibition or active forgetting. Moreover, this memory retrieval-concomitant active forgetting comes at the cost of genuine amnesic weakening of the inhibited episodes, a phenomenon referred to as retrieval-induced forgetting (RIF). In the present study, we introduce a novel characterization of our previously validated mouse model of EdM in terms of the existing active forgetting and RIF literature. We also introduce novel behavioral analyses of the deliberation processes elicited by EdM challenge and use detailed multi-factorial explorations to reveal how these processes are impacted by age, temporal retention demand, difficulty of EdM challenge, and anticipation of trial outcome. Our observations indicate that deliberation requires remembering while accurate anticipation--in which a critical age-related deficit is also observed--requires active forgetting. Our results represent a significant advance towards unifying our understanding of the neurocognitive processes underpinning everyday-like memory, RIF, mnemonic deliberation, anticipatory function, and how they all are impacted by the physiological ageing process. In parallel, we present preliminary results using a transgenic mouse model which point to a fundamental role for the endocannabinoid system (eCS) in active forgetting and EdM, thereby demonstrating that deeper investigation of previously characterized age-related decline of the eCS should be a pre-clinical priority with a view to developing treatments for age-related decline of EdM function.

animal behavior and cognition↗

bioRxiv2021

Autism Spectrum Disorder is a Risk Factor for PTSD-like Memory Formation

A rising concern in Autism Spectrum Disorder (ASD) is the heightened sensitivity to stress and trauma, the potential consequences of which have been overlooked, particularly upon the severity of the ASD traits. This study investigated the predisposition to, and impact of, Post-Traumatic Stress Disorder (PTSD) in ASD. We first demonstrated a reciprocal relationship between the two disorders and revealed that exposure to a mild stressful event induces PTSD-like memory in four mouse models of ASD. We also establish an unanticipated consequence of stress in this condition, showing that the formation of PTSD-like memory leads to the aggravation of the core traits associated with ASD. Such a susceptibility to developing PTSD-like memory in ASD stemmed from hyperactivation of the prefrontal cortex and altered fine-tuning of parvalbumin interneuron firing. We show that this traumatic memory can be treated by recontextualization, reducing the deleterious effects on the core symptoms of ASD. Overall, this study reveals multi-level neurobiological mechanisms that explain the increased vulnerability to develop PTSD in ASD. It provides a framework for future examination of the impact of PTSD-like memory in autism and offers new directions toward behavioral therapeutic interventions targeting traumatic memory in ASD.

neuroscience↗

bioRxiv2020

Loss of the Er81 Transcription Factor in Cholinergic Cells Alters Striatal Activity and Habit Formation

The finely-tuned activity of cholinergic interneurons (CINs) in the striatum is key for motor control, learning, and habit formation. Yet, the molecular mechanisms that determine their unique functional properties remain poorly explored. Using a combination of genetic and biochemical assays, in vitro and in vivo physiological characterisation, we report that selective ablation of the Er81 transcription factor leads to prominent changes in CIN molecular, morphological and electrophysiological features. In particular, the lack of Er81 amplifies intrinsic delayed-rectifier and hyperpolarization-activated currents, which subsequently alters the tonic and phasic activity of CINs. We further demonstrate that these alterations enhance their pause and time-locked responses to sensorimotor inputs in awake mice. Finally, this study reveals an Er81-dependent developmental mechanism in CINs essential for habit formation in adult mice. Highlights- The Er81 transcription factor is expressed in striatal cholinergic interneurons (CINs) - Conditional deletion of Er81 alters key molecular, morphological and electrophysiological properties of CINs in adult mice - Deletion of Er81 reduces the intrinsic excitability of CINs by upregulating delayed rectifier and hyperpolarization-activated currents - Deletion of Er81 alters in vivo striatal activity and habit formation

neuroscience↗