Schizophrenia is a debilitating psychiatric disorder that effects 1% of the population, with an additional 2-3% developing a schizoaffective disorder. SCZ patients exhibit a spectrum of cognitive deficits including defective episodic memory, present prior to the onset of psychosis and frequently expressed in relatives of affected individuals. Episodic memory formation is dictated in part by spatially tuned (place cell) activity of principal cells in the hippocampus. The biological mechanisms driving this learning capacity in the healthy hippocampus remain largely unknown, let alone their disruption in schizophrenia, leaving large gaps in our knowledge that need to be addressed. Using in vivo functional imaging in mouse dorsal hippocampal area CA1 during head-fixed during learning behaviors, we recently uncovered specific alterations in in vivo physiological properties of CA1 pyramidal cells in the Df(16)A+/? transgenic mouse model of 22q11.2 deletion syndrome, the largest known genetic risk to develop SCZ. Df(16)A+/? CA1 place cells exhibit reduced long-term stability, impaired context- related and lack of reward-related reorganization. A novel form of synaptic plasticity, termed behavioral time- scale synaptic plasticity (BTSP), has been found to drive rapid formation of spatially selective firing fields in CA1 pyramidal cells; notably, our preliminary studies suggest that this form of plasticity is dysregulated in Df(16)A+/? mice. We thus hypothesize that BTSP, a major form of plasticity that drives place cell-recruitment during learning, is disrupted by SCZ risk mutations. These findings at the neuronal population level provide entry points for dissecting the underlying cellular, molecular and microcircuit dysfunctions caused by schizophrenia risk mutations. To gain these mechanistic insights we will unite the complementary expertise of the Losonczy lab and the Gogos lab in etiologically valid genetic mouse models of neuropsychiatric disorders to carry out multiscale dissection of microcircuit, cellular and molecular pathophysiology of schizophrenia-related memory deficits in the adult mouse hippocampal CA1 circuitry.
Aim 1 is aimed at assessing altered synaptic plasticity in CA1 pyramidal cells during episodic learning in Df(16)A+/? mice.
Aim 2 deals with dissecting inhibitory microcircuit dynamics during episodic learning, while Aim 3 is focused at dissecting altered excitatory and neuromodulatory input dynamics to CA1 during episodic learning in Df(16)A+/? mice. Taken together, Aims 1-3 provide a tractable path to a deeper, mechanistic understanding of hippocampus-related cognitive memory deficits in schizophrenia.
Cognitive memory deficits are highly debilitating symptoms in schizophrenia. We propose the first attempt to comprehensively describe and understand cellular, molecular and microcircuit pathomechanisms of schizophrenia risk mutation-related episodic memory deficits in a genetic mouse model of schizophrenia. We will use cutting-edge, high-resolution recording and manipulation technologies in the hippocampal circuitry of behaving mice. These approaches are likely to yield major insights into the principles by which cellular, molecular and microcircuit alterations lead to cognitive memory dysfunctions associated with schizophrenia.
