Biology subjects

Large, C. H.

Publications and source records attributed to Large, C. H..

3 recordsLinked to original sources

bioRxiv2021

Kv3 channels contribute to the excitability of sub-populations of spinal cord neurons in lamina VII

Autonomic parasympathetic preganglionic neurons (PGN) drive contraction of the bladder during micturition but remain quiescent during bladder filling. This quiescence is postulated to be due to recurrent inhibition of PGN by fast-firing adjoining interneurons. Here, we defined four distinct neuronal types within lamina VII of the lumbosacral spinal cord, where PGN are situated, by combining whole cell patch clamp recordings with k-means clustering of a range of electrophysiological parameters. Additional morphological analysis separated these neuronal classes into parasympathetic preganglionic populations (PGN) and a fast firing interneuronal population. Kv3 channels are voltage-gated potassium channels (Kv) that allow fast and precise firing of neurons. We found that blockade of Kv3 channels by tetraethylammonium (TEA) reduced neuronal firing frequency and isolated high-voltage-activated Kv currents in the fast-firing population but had no effect in PGN populations. Furthermore, Kv3 blockade potentiated the local and descending inhibitory inputs to PGN indicating that Kv3-expressing inhibitory neurons are synaptically connected to PGN. Taken together, our data reveal that Kv3 channels are crucial for fast and regulated neuronal output of a defined population that may be involved in intrinsic spinal bladder circuits that underpin recurrent inhibition of PGN. Significance statementNeural circuits in the spinal cord and pons mediate the micturition reflex. The spinal cord drives bladder contraction during micturition through the activation of parasympathetic preganglionic neurons in lamina VII of the lumbosacral spinal cord. Despite the significant contribution of these neurons to a crucial physiological reflex, neurons in this region have been under-characterised. This study therefore elucidated and thoroughly characterised distinct neuronal populations in this lamina; we propose that these populations included a fast firing interneuron and subtypes of parasympathetic preganglionic neurons. Further investigation revealed the critical importance of Kv3 channels in the fast firing ability of the interneurons, as well as in synaptic release onto parasympathetic preganglionic neurons.

neuroscience↗

bioRxiv2021

Reducing voltage-dependent potassium channel Kv3.4 levels ameliorates synapse loss in a mouse model of Alzheimers disease

Synapse loss is associated with cognitive decline in Alzheimers disease (AD) and owing to their plastic nature, synapses are an ideal target for therapeutic intervention. Oligomeric amyloid beta (A{beta}) around amyloid plaques is known to contribute to synapse loss in mouse models and is associated with synapse loss in human AD brain tissue, but the mechanisms leading from A{beta} to synapse loss remain unclear. Recent data suggest that the fast-activating and -inactivating voltagegated potassium channel subtype 3.4 (Kv3.4) may play a role in A{beta}-mediated neurotoxicity. Here, we tested whether this channel could also be involved in A{beta} synaptotoxicity. Using adeno-associated virus and CRISPR (clustered regularly interspaced short palindromic repeats) technology, we reduced Kv3.4 expression in neurons of the somatosensory cortex of APP/PS1 mice. These mice express human familial AD associated mutations in amyloid precursor protein and presenilin 1 and develop amyloid plaques and plaque-associated synapse loss similar to that observed in AD brain. We observe that reducing Kv3.4 levels ameliorates dendritic spine loss and changes spine morphology compared to control virus. In support of translational relevance, Kv3.4 protein was observed in human AD and control brain and is associated with synapses in human iPSC-derived cortical neurons. Interestingly, we observe a decrease in Kv3.4 expression in iPSC derived cortical neurons when they are challenged with human Alzheimers disease derived brain homogenate. These results suggest that approaches to reduce Kv3.4 expression and/or function could be protective against A{beta}-induced synaptic alterations.

neuroscience↗

bioRxiv2021

Regulation of auditory fear discrimination by the novel Kv3 voltage-gated potassium channel modulator AUT00206

Psychiatric diseases like anxiety-related disorders and schizophrenia are characterized by impaired cognition and emotional regulation linked to corticolimbic disinhibition. Restoring the balance between excitation and inhibition in corticolimbic circuits may therefore ameliorate certain features of these disorders, such as inappropriately attributing affective salience to innocuous cues. Corticolimbic activity is tightly controlled by parvalbumin-expressing GABAergic interneurons, which also regulate fear discrimination. The voltage-gated potassium channels Kv3.1 and Kv3.2 are highly expressed in these neurons, therefore Kv3.1/3.2 modulation may have potential for treating disorders associated with cognitive and emotional dysregulation. We determined the effects of the novel Kv3.1/3.2 positive modulator AUT00206 on fear discrimination. Female rats underwent limited or extended auditory fear discrimination training that we previously showed leads to discrimination or generalization, respectively, based on passive fear responding (i.e. freezing). We also assessed darting as an active fear response. We found that limited training resulted in discrimination based on freezing, which was unaffected by AUT00206. In contrast, we found that extended training resulted in generalization based on freezing and the emergence of discrimination based on darting. Importantly, AUT00206 had dissociable effects on fear discrimination and expression with extended training. While AUT00206 mitigated generalization without affecting expression based on freezing, it reduced expression without affecting discrimination based on darting. Our results indicate that Kv3.1/3.2 modulation regulates the attribution of affective significance to threat- and safety-related cues in a response-specific manner. This suggests that targeting Kv3.1 and Kv3.2 channels may provide a promising avenue for treating cognitive and emotional dysregulation in psychiatric disease.

neuroscience↗