Biology subjects

Assali, A.

Publications and source records attributed to Assali, A..

4 recordsLinked to original sources

bioRxiv2024

Point contact-restricted cAMP signaling controls ephrin-A5-induced axon repulsion

Signal transduction downstream of axon guidance molecules is essential to steer developing axons. Second messengers including cAMP are key molecules shared by a multitude of signaling pathways and are required for a wide range of cellular processes including axon pathfinding. Yet, how these signaling molecules achieve specificity for each of their downstream pathways remains elusive. Subcellular compartmentation emerged as a flexible strategy to reach such a specificity. Here, we show that point contact-restricted cAMP signals control ephrin-A5-evoked axon repulsion in vitro by modulating Focal Adhesion Kinase phosphorylation and the assembly and disassembly rate of point contacts. Consistently, preventing point contact-specific cAMP signals, in developing retinal ganglion cells in vivo alters the refinement of their terminal axonal arbor in the brain. Altogether, our study identifies point contacts as a compartment containing a local cAMP signal required for ephrin-A5-dependent axon guidance and highlights the crucial role of such subcellularly restricted second messenger signals in the wiring of neuronal circuits.

developmental biology↗

bioRxiv2022

Chronic methamphetamine administration produces cognitive deficits through augmentation of GABAergic synaptic transmission in the prefrontal cortex

BACKGROUNDChronic methamphetamine (METH) abuse is associated with the emergence of cognitive deficits and hypofrontality, a pathophysiological marker of many neuropsychiatric disorders that is produced by altered balance of local excitatory and inhibitory synaptic transmission. However, there is a dearth of information regarding the cellular and synaptic mechanisms underlying METH-induced cognitive deficits and associated hypofrontal states. METHODSRats went through a METH sensitization regime or saline (SAL) consisting of 14 days of METH treatment (day 1 and 14, 1 mg/kg; days 2-13, 5 mg /kg) followed by 7-10 days of home cage abstinence. Temporal Order Memory and Working Memory tests, chemogenetic experiments as well as whole-cell patch recordings on prelimbic PFC ex vivo slices were performed during abstinence. RESULTSWe find here that repeated METH administration in rats produces deficits in working memory and increases in inhibitory synaptic transmission onto pyramidal neurons in the prefrontal cortex (PFC). The increased PFC inhibition is detected by an increase in spontaneous and evoked inhibitory postsynaptic synaptic currents (IPSCs), an increase in GABAergic presynaptic function, and a shift in the excitatory-inhibitory balance onto PFC deep-layer pyramidal neurons. We find that pharmacological blockade of D1 dopamine receptor function reduces the METH-induced augmentation of IPSCs, suggesting a critical role for D1 dopamine signaling in METH-induced hypofrontality. In addition, chronic METH administration increases the intrinsic excitability of parvalbumin-positive interneurons, a key local interneuron population in PFC that controls inhibitory tone. Using a cell type-specific chemogenetic approach, we show that increasing PV+FSI activity in the PFC is necessary and sufficient to cause deficits in temporal order memory similar to those induced by METH. CONCLUSIONTogether, our findings reveal that chronic METH exposure increases PFC inhibitory tone through a D1 dopamine signaling-dependent potentiation of inhibitory synaptic transmission, and that reduction of PV+FSI activity can rescue METH-induced cognitive deficits, suggesting a potential therapeutic approach to treating cognitive symptoms in patients suffering from methamphetamine use disorder.

neuroscience↗

bioRxiv2022

EphB1 controls proper long-range cortical axon guidance through a cell non-autonomous role in GABAergic cells

EphB1 is required for proper guidance of cortical axon projections during brain development, but how EphB1 regulates this process remains unclear. We show here that EphB1 conditional knockout (cKO) in GABAergic cells (Vgat-Cre or Dlx1/2-Cre), but not in cortical excitatory neurons (Emx1-Cre), reproduced the cortical axon guidance defects observed in global EphB1 KO mice. Interestingly, in EphB1 cKOVgat mice, the misguided axon bundles contained comingled striatal GABAergic and somatosensory cortical glutamatergic axons. In wildtype mice, somatosensory axons also co-fasciculated with striatal axons notably in the globus pallidus, suggesting that a subset of glutamatergic cortical axons normally follows long-range GABAergic axons to reach their targets. Surprisingly, the ectopic axons in EphB1 KO mice were juxtaposed to major blood vessels. However, conditional loss of EphB1 in endothelial cells (Tie2-Cre), or in mural and oligodendrocyte precursor cells (Cspg4-Cre) did not produce the axon guidance defects, suggesting that EphB1 in GABAergic neurons normally promotes avoidance of these ectopic axons from following the developing vasculature. Together, our data reveal a new role for EphB1 in GABAergic neurons to influence proper cortical glutamatergic axon guidance during brain development.

neuroscience↗

bioRxiv2019

MEF2C hypofunction in neuronal and neuroimmune populations cooperate to produce MEF2C haploinsufficiency syndrome-like behaviors in mice

Microdeletions of the MEF2C gene are linked to a syndromic form of autism termed MEF2C haploinsufficiency syndrome (MCHS). Here, we show that MCHS-associated missense mutations cluster in the conserved DNA binding domain and disrupt MEF2C DNA binding. DNA binding-deficient global Mef2c heterozygous mice (Mef2c-Het) display numerous MCHS-like behaviors, including autism-related behaviors, as well as deficits in cortical excitatory synaptic transmission. We find that hundreds of genes are dysregulated in Mef2c-Het cortex, including significant enrichments of autism risk and excitatory neuron genes. In addition, we observe an enrichment of upregulated microglial genes, but not due to neuroinflammation in the Mef2c-Het cortex. Importantly, conditional Mef2c heterozygosity in forebrain excitatory neurons reproduces a subset of the Mef2c-Het phenotypes, while conditional Mef2c heterozygosity in microglia reproduces social deficits and repetitive behavior. Together our findings suggest that MEF2C regulates typical brain development and function through multiple cell types, including excitatory neuronal and neuroimmune populations.

neuroscience↗