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Neurosci."],"abstract":"<jats:p>Duchenne muscular dystrophy (DMD) is generally regarded as a muscle-wasting disease. However, human patients and animal models of DMD also frequently display non-progressive cognitive deficits and high comorbidity with neurodevelopmental disorders, suggesting impaired central processing. Previous studies have identified the cerebellar circuit, and aberrant inhibitory transmission in Purkinje cells, in particular, as a potential site of dysfunction in the central nervous system (CNS). In this work, we investigate potential dysfunction in the output of the cerebellum, downstream of Purkinje cell (PC) activity. We examined synaptic transmission and firing behavior of excitatory projection neurons of the cerebellar nuclei, the primary output of the cerebellar circuit, in juvenile wild-type and <jats:italic>mdx<\/jats:italic> mice, a common mouse model of DMD. Using immunolabeling and electrophysiology, we found a reduced number of PC synaptic contacts, but no change in postsynaptic GABA<jats:sub>A<\/jats:sub> receptor expression or clustering in these cells. Furthermore, we found that the replenishment rate of synaptic vesicles in Purkinje terminals is reduced in <jats:italic>mdx<\/jats:italic> neurons, suggesting that dysfunction at these synapses may be primarily presynaptic. We also found changes in the excitability of cerebellar nuclear neurons. Specifically, we found greater spontaneous firing but reduced evoked firing from a hyperpolarized baseline in <jats:italic>mdx<\/jats:italic> neurons. Analysis of action potential waveforms revealed faster repolarization and greater after-hyperpolarization of evoked action potentials in <jats:italic>mdx<\/jats:italic> neurons, suggesting an increased voltage- or calcium- gated potassium current. We did not find evidence of dystrophin protein or messenger RNA (mRNA) expression in wild-type nuclear neurons, suggesting that the changes observed in these cells are likely due to the loss of dystrophin in presynaptic PCs. Together, these data suggest that the loss of dystrophin reduces the dynamic range of synaptic transmission and firing in cerebellar nuclear neurons, potentially disrupting the output of the cerebellar circuit to other brain regions and contributing to cognitive and neurodevelopmental deficits associated with DMD.<\/jats:p>","DOI":"10.3389\/fncel.2022.926518","type":"journal-article","created":{"date-parts":[[2022,7,5]],"date-time":"2022-07-05T08:07:21Z","timestamp":1657008441000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":14,"title":["Altered Synaptic Transmission and Excitability of Cerebellar Nuclear Neurons in a Mouse Model of Duchenne Muscular Dystrophy"],"prefix":"10.3389","volume":"16","author":[{"given":"Tabita","family":"Kreko-Pierce","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jason R.","family":"Pugh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2022,7,5]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"827","DOI":"10.1016\/S0896-6273(00)80598-X","article-title":"Polarity of long-term synaptic gain change is related to postsynaptic spike firing at a cerebellar inhibitory synapse","volume":"21","author":"Aizenman","year":"1998","journal-title":"Neuron"},{"key":"B2","doi-asserted-by":"publisher","first-page":"177","DOI":"10.1111\/j.1600-0854.2006.00519.x","article-title":"Processing and assembly of the dystrophin glycoprotein complex","volume":"8","author":"Allikian","year":"2007","journal-title":"Traffic"},{"key":"B3","doi-asserted-by":"publisher","first-page":"280","DOI":"10.1016\/S0006-8993(03)03018-X","article-title":"Altered inhibitory input to Purkinje cells of dystrophin-deficient mice","volume":"982","author":"Anderson","year":"2003","journal-title":"Brain Res."},{"key":"B4","doi-asserted-by":"publisher","first-page":"289","DOI":"10.1016\/j.brainres.2004.06.011","article-title":"Long-term depression is reduced in cerebellar Purkinje cells of dystrophin-deficient mdx mice","volume":"1019","author":"Anderson","year":"2004","journal-title":"Brain Res."},{"key":"B5","doi-asserted-by":"publisher","first-page":"2318","DOI":"10.1523\/JNEUROSCI.4322-06.2007","article-title":"Transgenic mouse lines subdivide medial vestibular nucleus neurons into discrete, neurochemically distinct populations","volume":"27","author":"Bagnall","year":"2007","journal-title":"J. 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