Dendritic spine abnormalities correlate with behavioral and cognitive deficits in mouse models of Lafora disease

Abstract

Lafora disease (LD) is a genetic and fatal form of neurodegenerative disorder characterized by myoclonic epilepsy and cognitive deficits. LD is caused by loss‐of‐function mutations in the EPM2A or the NHLRC1 gene. A major hallmark of LD is the presence of abnormal glycogen aggregates in neurons and other tissues. Functional studies on the genes have, therefore, mostly focused on glycogen metabolism. The physiological basis of cognitive deficits in LD is thus largely unexplored. Alterations in dendritic spine morphology are known in neurodevelopmental and neuropsychiatric disorders. We, therefore, analyzed the dendritic spine morphologies in pyramidal neurons of the hippocampal and Cortical layer V of the Epm2a or Nhlrc1 knockout mice brain. We found a significant increase in the density, length, and reduction in the width of the dendritic spines in Postnatal day 21 to 12‐month‐old LD animals. Similar observations were made in the primary cultures of neurons derived from the hippocampi of the embryonic brain, suggesting that the aberrant spine phenotype could be a developmental defect in LD. We also looked at the cognitive and behavioral deficits as a possible readout of the spine abnormalities. The LD animals exhibited hyperactivity, reduced anxiety‐like behavior, and deficits in the spatial and nonspatial memory. Such abnormalities were seen in the younger (1–2 months) as well as the older (7–8 months) age groups. Taken together, our results suggest that the dendritic spine abnormalities are primary developmental defects in the LD model and these defects might underlie some of the symptoms, including cognitive deficits, in LD.

Pharmacological modulation of glutamatergic and neuroinflammatory pathways in a Lafora disease mouse model

“…1C)] but they also made a greater number of entries into the center [e.g., Epm2b-/-(21.92 ± 2.53) and WT (16.92 ± 2.19, p=0.239, d=-0.56 medium) (Table S1)]. Although not statistically signi cant, both behaviors pointed out a tendency to decrease anxiety and hyperactive behavior in Epm2b-/mice, as already reported by other authors [16], [17]. After the anti-in ammatory treatments (resveratrol and minocycline), the % traveled distance of Epm2b-/in the center was decreased signi cantly by resveratrol (14.64 ± 2.15, p=0.011*, d=0.80 large) (Fig.…”

“…Laforin and malin assemble into a functional complex involved in glycogen metabolism, as part of a quality control mechanism to prevent the accumulation of insoluble glycogen [9], [10]. LD knockout (KO) mouse models with a complete loss of function of laforin (Epm2a-/-) [11] or malin (Epm2b-/-) [12], [13], [14] partially mimic human symptoms such as early PGs accumulation in muscle, heart, and brain from 2-months of age [11], [14]; they also show slight impairment of motor coordination, abnormal postures of the hindlimb, memory defects and spontaneous myoclonic seizures evident from 9 months of age [11], [14], [15]; nally, they present enhanced excitability [11] with hyperactive behavior from 1 to 11-month-old [16], [17]. At the histopathological level, the brain of LD mouse models shows neurodegeneration with loss of GABAergic and parvalbumin+ (PV+) neurons and dendritic abnormalities in pyramidal neurons [16], [17], [18], massive astrogliosis accumulating PGs [19], [20], as well as an early neuroin ammatory status from 3 months of age [21], [22].…”

Pharmacological Modulation of Glutamatergic and Neuroinflammatory Pathways in a Lafora Disease Mouse Model

“…At the histopathological level, the brain of LD mouse models shows neurodegeneration with loss of GABAergic and parvalbumin + (PV +) neurons and dendritic abnormalities in pyramidal neurons [16][17][18], massive astrogliosis accumulating PGs [19,20], as well as an early neuroinflammatory status from 3 months of age [21,22]. Due to the scarcity of accessing to human brain samples from Lafora disease patients, only the accumulation of insoluble polyglucosan inclusions (PGs) has been confirmed in the LD human brains [2,3].…”

“…LD knockout (KO) mouse models with a complete loss of function of laforin ( Epm2a − / − ) [ 11 ] or malin ( Epm2b − / − ) [ 12 – 14 ] have been used to understand LD pathophysiology. Although they do not fully reproduce human pathophysiology since they do not present spontaneous seizures and they do not die as the human patients do, they partially mimic human symptoms such as early PG accumulation in muscle, heart, and brain from 2 months of age [ 11 , 14 ]; they also show slight impairment of motor coordination, abnormal postures of the hindlimb, memory defects, and spontaneous myoclonic seizures evident from 9 months of age [ 11 , 14 , 15 ]; finally, they present enhanced excitability [ 11 ] with hyperactive behavior from 1 to 11 months old [ 16 , 17 ].…”

Ayurvedic formulations amalaki rasayana and rasa sindoor improve age-associated memory deficits in mice by modulating dendritic spine densities

“…The OFT was performed to assess the anxiety of open spaces in mice as described previously [ 31 ] with minor modifications. The OFT apparatus consisted of an open arena of 40 cm × 40 cm, enclosed by 40 cm high walls.…”