Region-specific role of LRRTM1 in the organization of glutamatergic synapses in mediodorsal nucleus of the thalamus and hippocampal dorsal CA1 region
| dc.contributor.author | Karimi, Benyamin | |
| dc.contributor.examiningcommittee | Jackson, Michael (Pharmacology and Therapeutics) | en_US |
| dc.contributor.examiningcommittee | Cowley, Kris (Physiology and Pathophysiology) | en_US |
| dc.contributor.examiningcommittee | Kirouac, Gilbert (Oral Biology) | en_US |
| dc.contributor.examiningcommittee | Swayne, Leigh Anne (University of Victoria) | en_US |
| dc.contributor.supervisor | Siddiqui, Tabrez J. (Physiology and Pathophysiology) | en_US |
| dc.date.accessioned | 2022-02-15T15:08:46Z | |
| dc.date.available | 2022-02-15T15:08:46Z | |
| dc.date.copyright | 2022-02-14 | |
| dc.date.issued | 2021-12-20 | en_US |
| dc.date.submitted | 2022-02-10T19:52:53Z | en_US |
| dc.date.submitted | 2022-02-15T02:21:24Z | en_US |
| dc.degree.discipline | Physiology and Pathophysiology | en_US |
| dc.degree.level | Doctor of Philosophy (Ph.D.) | en_US |
| dc.description.abstract | Synapse organizer proteins are essential components of chemical synapses. These proteins are fundamental for development, organization, and function of chemical synapses. Copy number variations or loss of function mutations in the genes encoding these proteins can lead to development of variety of neuropsychiatric diseases. Leucine Rich Repeat Transmembrane neuronal proteins (LRRTMs) are a family of four glutamatergic synapse organizers with distinct expression patterns in mammalian brain. LRRTM1 is a paternally imprinted gene, implicated in handedness and schizophrenia. LRRTM1 is strongly associated with schizophrenia and is highly expressed in the thalamus, prefrontal cortex, and hippocampal CA and dentate gyrus regions. Using region-specific deletion of Lrrtm1 in mediodorsal nucleus of the thalamus and hippocampal dorsal CA1 we have shown the importance of LRRTM1 in organization of PFC-MD synapses and integrity of MD-PFC circuit. We have also shown that LRRTM1 is essential for function of CA3-CA1 circuit and its deletion results in disruption of dorsal-CA1-associated behaviour in mice. Conditional deletion of Lrrtm1 in the MD in adult mice reduced excitatory synaptic function and caused a parallel reduction in the afferent synaptic activity of the PFC, which was reversed by the reintroduction of LRRTM1 in the MD. Conditional deletion of Lrrtm1 in the dorsal CA1 in adult mice reduced synaptic transmission and caused a deficit in long-term potentiation in the stratum radiatum but not stratum lacunosum moleculare. The deficits were reversed by the reintroduction of LRRTM1 or perfusion with GluR23Y. Our results indicate that chronic reduction of synaptic strength in the MD by targeted deletion of Lrrtm1 functionally disengages the MD from the PFC and may account for cognitive, social, and sensorimotor gating deficits, III reminiscent of schizophrenia. Our results indicate that chronic reduction of synaptic strength in the dorsal CA1 by targeted deletion of Lrrtm1 functionally disengages the CA3 from the CA1 and may account for contextual memory and social interaction deficits observed in several neuropsychological disorders. | en_US |
| dc.description.note | March 2022 | en_US |
| dc.identifier.uri | http://hdl.handle.net/1993/36304 | |
| dc.rights | open access | en_US |
| dc.subject | Schizophrenia | en_US |
| dc.subject | Synapse organizers | en_US |
| dc.subject | Hippocampus | en_US |
| dc.subject | Mediodorsal Thalamus | en_US |
| dc.title | Region-specific role of LRRTM1 in the organization of glutamatergic synapses in mediodorsal nucleus of the thalamus and hippocampal dorsal CA1 region | en_US |
| dc.type | doctoral thesis | en_US |