Biology subjects

McKinney, R. A.

Publications and source records attributed to McKinney, R. A..

8 recordsLinked to original sources

bioRxiv2026

Mistrafficking of KCC2 promotes hyperexcitability in hippocampal circuitry in a murine model of Christianson Syndrome

How endosomal trafficking shapes inhibitory neurotransmission remains poorly understood, despite both processes being linked independently to epilepsy and neurodevelopmental disease. Christianson syndrome (CS), an X-linked neurodevelopmental disorder, represents a potential tractable condition to investigate such coupled processes. CS is caused by loss-of-function mutations in the SLC9A6 gene which encodes the organellar (Na+, K+)/H+ exchanger NHE6 isoform whose loss overacidifies recycling endosomes and disrupts cargo delivery. Prior work has emphasized NHE6's role in excitatory neurons and glia; whether endosomal dysfunction reshapes inhibitory circuits and thereby drives the early treatment-resistant epilepsy that defines CS has not been addressed. Using Nhe6-/Y mice, we identify a previously unrecognized endosomal-to-inhibitory axis: NHE6 is required for the surface delivery and stability of the neuron-specific potassium-chloride co-transporter KCC2 (encoded by SLC12A5) that sets the driving force for GABAergic inhibition. Loss of NHE6 produces developmental downregulation and mistargeting of KCC2 in hippocampal neurons, impaired chloride homeostasis, and circuit-level hyperexcitability in response to a subthreshold convulsant challenge. These results recast CS epilepsy not as a downstream consequence of excitatory dysfunction but as a primary failure of inhibitory development driven by endosomal mistrafficking. More broadly, they establish endosomal pH regulation as a determinant of KCC2 biology; a node implicated across genetic and acquired epilepsies. Pharmacologically restoring KCC2 function therefore offers a mechanism-based therapeutic strategy for CS, and likely for the broader class of disorders in which endosomal trafficking and inhibitory imbalance converge.

neuroscience↗

bioRxiv2026

Symptom Dimension-Specific Neurotransmitter Correlates of Psychopathology and Cognition in Early Psychosis

Extended duration of under-treated psychosis (DUP) is among the strongest predictors of poor outcome, yet diagnostic heterogeneity impedes treatment matching, with approximately 50% of patients failing to respond to first-line antipsychotics. Negative symptoms and cognitive impairment are particularly refractory, lacking effective pharmacological treatments. Identifying neurotransmitter systems associated with specific symptom dimensions could accelerate targeted therapeutic development and reduce DUP. We applied Partial Least Squares correlation (PLSc) to derive whole-brain resting-state functional connectivity (RSFC) and anatomical (cortical thickness and subcortical volume) signatures associated with five psychopathology dimensions (positive symptoms, negative symptoms, general psychopathology, mania, and cognition) in a transdiagnostic sample from the Human Connectome Project-Early Psychosis (HCP-EP; n=124). We tested associations with potential confounds including antipsychotic medication dosage and substance use. Signatures were spatially correlated with 21 Positron Emission Tomography (PET)-derived receptor and transporter maps across 9 neurotransmitter systems using the neuromaps toolbox. Significant RSFC signatures emerged for positive symptoms, negative symptoms, general psychopathology, and cognition, but not mania. The negative symptom RSFC signature correlated with norepinephrine transporter (NET; {rho}=.40, q=.030) and vesicular acetylcholine transporter (VAChT; {rho}=.38, q=.048) distributions. The cognition signature similarly correlated with VAChT ({rho}=.48, q=.025). Anatomical signatures were associated with positive symptoms, general psychopathology, and cognition, but were more susceptible to confounding by medication and substance use. No significant receptor associations were detected for anatomical signatures. These findings implicate cholinergic and noradrenergic systems as molecular targets for negative symptoms and cognitive impairment, supporting prioritization of these systems in pharmacotherapy development in early psychosis.

neuroscience↗

bioRxiv2026

Zebrin molecular identity and cerebellar location determine Purkinje cell vulnerability in Christianson syndrome mice

Ataxia is a major characteristic feature in Christianson syndrome, where Purkinje cells in the anterior cerebellar vermis are vulnerable to degeneration while those in the posterior vermis are resilient. Here, we provide a temporal study of changes in Purkinje cell function, cell vulnerability and innervation of cerebellar nuclei in a mouse model of Christianson syndrome. Purkinje cells express certain molecules in a patterned manner across the cerebellum, such as aldolase C/zebrin-II (zebrin). We show that zebrin patterning appears normal before disease onset in Christianson syndrome mice with no apparent cell death, similar to what has been reported in patients. We observe rapid Purkinje cell death in the anterior lobe of Christianson syndrome mice that is exclusive to zebrin-negative Purkinje cells, with zebrin-positive Purkinje cells showing resilience. Intrinsic firing deficits exclusively in the anterior cerebellum are observed at the same time as the first observed cell death in the anterior cerebellum. In contrast, posterior Purkinje cells degenerated later, but zebrin-negative and zebrin-positive cells were equally susceptible to degeneration. Purkinje cells innervation in the cerebellar nuclei was also lost in Christianson syndrome mice in a region-specific manner: neurons in the anterior cerebellar nuclei, with predominantly zebrin-negative Purkinje cells inputs, displayed dramatic loss of Purkinje cells innervation, while neurons in the posterior cerebellar nuclei, innervated by both zebrin-negative and zebrin-positive terminals, showed greater resiliency. Together, our results highlight that cerebellar location and zebrin molecular identity appear important to the vulnerability of Purkinje cells and their innervation in the cerebellar nuclei in Christianson syndrome. HIGHLIGHTSO_LIFirst study showing Purkinje cell intrinsic firing alterations in Christianson syndrome mice. C_LIO_LIZebrin patterning appears normal before disease onset in Christianson syndrome mice. C_LIO_LIPurkinje cell firing deficits and death start at post-natal day 35 only in the anterior cerebellum in a Christianson syndrome mouse model. C_LIO_LIZebrin-negative and zebrin-positive Purkinje cells in the posterior cerebellum are initially resilient but are both equally susceptible to Purkinje cell death at later stages of the disorder. C_LIO_LIZebrin-negative Purkinje cell inputs to the anterior cerebellar nuclei are lost, while zebrin-positive inputs remain. C_LIO_LIThe pattern of Purkinje cell death in Christianson Syndrome is similar to that of many rare ataxias, suggesting a comparable underlying pathophysiology, which could lead to common therapeutic targets. C_LI

neuroscience↗

bioRxiv2023

Eta-secretase-like processing of the amyloid precursor protein (APP) by RHBDL4

The amyloid precursor protein (APP) has been extensively studied with regards to its contribution to the pathology of Alzheimers disease. APP is an ubiquitously expressed type I transmembrane protein synthesized in the endoplasmic reticulum (ER) and translocated to the plasma membrane where it undergoes proteolytic cleavages by several identified proteases. Conversely to other known proteases, we previously elucidated human rhomboid protease RHBDL4 as a novel APP processing enzyme where several cleavages likely occur already in the ER. Interestingly, the pattern of RHBDL4-derived large APP C-terminal fragments resemble those generated by the {eta}-secretase or MT5-MMP, which was described to generate so called A{eta} fragments. The similarity in large APP C-terminal fragments between both proteases raised the question whether RHBDL4 may contribute to {eta}-secretase activity and A{eta}-like fragments. Here, we identified two cleavage sites of RHBDL4 in APP by mass spectrometry, which, intriguingly, lie in close proximity to the cleavage sites of MT5-MMP. Indeed, we observed that RHBDL4 generates A{eta}-like fragments in vitro without contributions of -, {beta}-, or {gamma}-secretases. Such A{eta}-like fragments are likely generated in the ER since RHBDL4-derived APP-C-terminal fragments do not reach the cell surface. Inherited, familial APP mutations appear to not affect this processing pathway. In RHBDL4 knockout mice, we observed increased cerebral full length APP levels in comparison to WT brains in support of RHBDL4 being a physiologically relevant protease for APP. Furthermore, we found secreted A{eta} fragments in dissociated mixed cortical cultures from wild type mice, however significantly less A{eta} fragments in cultures from RHBDL4 knockout mice. Our data underscores that RHBDL4 contributes to {eta}-secretease-like processing of APP and that RHBDL4 is a physiologically relevant protease for APP.

biochemistry↗

bioRxiv2023

Synaptopodin is required for long-term depression at Schaffer collateral-CA1 synapses

Synaptopodin (SP), an actin-associated protein found in telencephalic neurons, affects synaptic and structural plasticity. While being required for longterm depression (LTD) mediated by metabotropic glutamate receptor (mGluR-LTD), little is known about its role in other forms of LTD induced by low frequency stimulation (LFS-LTD) or spike-timing dependent plasticity (STDP). Using SP-deficient mice (SPKO), we have here demonstrated that the presence of SP is mandatory for normal LTD expression. On the contrary, long-term potentiation (LTP), albeit diminished in SPKO, is still present and can be easily recovered by increasing the stimulation frequency. Our study shows, for the first time, the role of SP in a more physiological form of induction of synaptic plasticity.

neuroscience↗

bioRxiv2023

Loss of synaptopodin impairs mGluR5 and protein synthesis dependent mGluR-LTD at CA3-CA1 synapses

Metabotropic glutamate receptor-dependent long-term depression (mGluR-LTD) is an important form of synaptic plasticity that occurs in many regions of the CNS and is the underlying mechanism for several learning paradigms. In the hippocampus, mGluR-LTD is manifested by the weakening of synaptic transmission and elimination of dendritic spines. Interestingly, not all spines respond or undergo plasticity equally in response to mGluR-LTD. A subset of dendritic spines containing synaptopodin (SP), an actin-associated protein, are critical for mGluR-LTD and protect spines from elimination through mGluR1 activity. The precise cellular function of SP is still enigmatic and it is still unclear how SP contributes to the functional aspect of mGluR-LTD despite of its modulation on the structural plasticity. In the present study, we show that the lack of SP impairs mGluR-LTD by negatively affecting the mGluR5-dependent activity. Such impairment of mGluR5 activity is accompanied by a significant decrease of surface mGluR5 level in SP knockout (SPKO) mice. Intriguingly, the remaining mGluR-LTD becomes a protein synthesis-independent process in the SPKO and is mediated instead by endocannabinoid signaling. These data show for the first time that the postsynaptic protein SP can regulate the locus of expression of mGluR-LTD and provide insight to our understanding of spine/synapse-specific plasticity. Significance statementHippocampal group I metabotropic glutamate receptor dependent long-term depression (mGluR-LTD), a form of learning and memory, is misregulated in many murine models of neurodevelopmental disorders. Despite extensive studies there is a paucity of information on the molecular mechanism underlying mGluR-LTD. Previously, we reported that loss of synaptopodin, an actin-associated protein found in a subset of mature dendritic spines, impairs mGluR-LTD. In the current study, we uncover the molecular and cellular deficits involved. We find that synaptopodin is required for the mGluR5-Homer interaction and uncover synaptopodin as a molecular switch for mGluR-LTD expression, as mGluR-LTD becomes protein synthesis-independent and relies on endocannabinoid signaling in synaptopodin knock-out. This work provides insight into synaptopodin as a gatekeeper to regulate mGluR-LTD at hippocampal synapses.

neuroscience↗

bioRxiv2021

Stabilization of spine Synaptopodin by mGluR1 is required for mGluR-LTD

Dendritic spines, actin-rich protrusions forming the postsynaptic sites of excitatory synapses, undergo activity-dependent molecular and structural remodeling. Activation of group 1 metabotropic glutamate receptors - mGluR1 and mGluR5 - by synaptic or pharmacological stimulation, induces LTD but whether this is accompanied with spine elimination remains unresolved. A subset of telencephalic mushroom spines contains the spine apparatus (SA), an enigmatic organelle composed of stacks of smooth endoplasmic reticulum, whose formation depends on the expression of the actin-bundling protein Synaptopodin. Allocation of Synaptopodin to spines appears governed by cell-intrinsic mechanisms as the relative frequency of spines harboring Synaptopodin is conserved in vivo and in vitro. Here we show that expression of Synaptopodin/SA in spines is required for induction of mGluR-LTD at Schaffer collateral-CA1 synapses. Post-mGluR-LTD, mushroom spines lacking Synaptopodin/SA are selectively lost whereas spines harboring it are preserved, a process dependent on activation of mGluR1 but not mGluR5. Mechanistically, we find that mGluR1 supports physical retention of Synaptopodin within excitatory spine synapses during LTD while triggering lysosome-dependent degradation of the protein residing in dendritic shafts. Together, these results reveal a cellular mechanism, dependent on mGluR1, which enables selective preservation of stronger spines containing Synaptopodin/SA while eliminating weaker ones and potentially countering spurious strengthening by de novo recruitment of Synaptopodin. Overall our results identify spines with Synaptopodin/SA as the locus of mGluR-LTD and underscore the importance of the molecular microanatomy of spines in synaptic plasticity.

neuroscience↗

bioRxiv2018

Activity-dependent netrin-1 secretion drives synaptic insertion of GluA1-containing AMPA receptors in the hippocampus.

Dynamic trafficking of -amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid glutamate receptors (AMPARs) to synapses is critical for activity-dependent synaptic plasticity underlying learning and memory, however the identity of key molecular effectors remains elusive. Here, we demonstrate that membrane depolarization and N-methyl-D-aspartate receptor (NMDAR) activation triggers secretion of the chemotropic guidance cue netrin-1 from dendrites. Using selective genetic deletion, we show that netrin-1 expression by excitatory neurons is required for NMDAR-dependent long-term potentiation (LTP) in the adult hippocampus. Further, we demonstrate that application of exogenous netrin-1 is sufficient to trigger the potentiation of excitatory glutamatergic transmission at hippocampal Schaffer collateral synapses via Ca2+-dependent recruitment of GluA1-containing AMPARs, promoting the maturation of immature or nascent synapses. These findings identify a central role for activity-dependent release of netrin-1 as a critical effector of synaptic plasticity in the adult hippocampus.

neuroscience↗