Proportional loss of parvalbumin‐immunoreactive synaptic boutons and granule cells from the hippocampus of sea lions with temporal lobe epilepsy

Abstract

One in 26 people develop epilepsy and in these temporal lobe epilepsy (TLE) is common. Many patients display a pattern of neuron loss called hippocampal sclerosis. Seizures usually start in the hippocampus but underlying mechanisms remain unclear. One possibility is insufficient inhibition of dentate granule cells. Normally parvalbumin‐immunoreactive (PV) interneurons strongly inhibit granule cells. Humans with TLE display loss of PV interneurons in the dentate gyrus but questions persist. To address this, we evaluated PV interneuron and bouton numbers in California sea lions (Zalophus californianus) that naturally develop TLE after exposure to domoic acid, a neurotoxin that enters the marine food chain during harmful algal blooms. Sclerotic hippocampi were identified by the loss of Nissl‐stained hilar neurons. Stereological methods were used to estimate the number of granule cells and PV interneurons per dentate gyrus. Sclerotic hippocampi contained fewer granule cells, fewer PV interneurons, and fewer PV synaptic boutons, and the ratio of granule cells to PV interneurons was higher than in controls. To test whether fewer boutons was attributable to loss versus reduced immunoreactivity, expression of synaptotagmin‐2 (syt2) was evaluated. Syt2 is also expressed in boutons of PV interneurons. Sclerotic hippocampi displayed proportional losses of syt2‐immunoreactive boutons, PV boutons, and granule cells. There was no significant difference in the average numbers of PV‐ or syt2‐positive boutons per granule cell between control and sclerotic hippocampi. These findings do not address functionality of surviving synapses but suggest reduced granule cell inhibition in TLE is not attributable to anatomical loss of PV boutons.

Hippocampal Sclerosis in Pilocarpine Epilepsy: Survival of Peptide-Containing Neurons and Learning and Memory Disturbances in the Adult NMRI Strain Mouse

“…The estimated decrease in the PV-IR cell population was about 50% in our experiments. The literature data support this observation [22,34,46]. The presence of scattered PV-IR astrocytes in the sclerosed regions is a new finding.…”

Pericardial Injection of Kainic Acid Induces a Chronic Epileptic State in Larval Zebrafish

“…KA together with its analog domoic acid are well-known to induce epilepsy in many different animals (Ramsdell and Gulland, 2014 ). For instance, sea lions exposed to domoic acid due to algal blooms develop hippocampal sclerosis and seizures (Cameron et al, 2019 ). Similarly, domoic acid induced seizure behavior, progressing from a brief hyperactive response into paralysis with tremors isolated in the tail, in 7 dpf zebrafish larvae via water immersion (Tiedeken and Ramsdell, 2009 ).…”

Epilepsy Benchmarks Area I: Understanding the Causes of the Epilepsies and Epilepsy-Related Neurologic, Psychiatric, and Somatic Conditions

“…Interneuronopathies can be broadly defined as those conditions in which epilepsy or neuropsychiatric comorbidities arise as a consequence of either developmental or functional changes in interneurons. Alterations in interneuron migration or numbers have been identified in multiple epilepsy mouse models, including mice with deletions of Cntnap2, 35 Wwox, 36 and Syn-gap1, 37 as well as in certain models of acquired epilepsy, 38,39 and after traumatic brain injury. 40,41 Epilepsy that occurs in Dravet syndrome associated with pathogenic variants in SCN1A may also be classified in this category based on evidence that interneurons in Scn1a heterozygous mice display a selective decrease in excitability, and selective deletions of Scn1a in interneurons are sufficient to recapitulate the spectrum of Dravet-related phenotypes.…”